General

The bombesin (Bn) receptor family is a member of the G protein-coupled receptor superfamily and consists of three subtypes of receptors: the neuromedin B (NMB) receptor (BB₁ receptor), the gastrin-releasing peptide (GRP) receptor (BB₂ receptor) and the orphan receptor, bombesin receptor subtype 3 (BRS-3) (BB₃ receptor) [57,87,92,122]. The unusual name of this class of receptors comes from the fact that bombesin and many of the other naturally occurring peptides in this peptide family were isolated from the skin of various frogs and were named after the genus of the frog from which they were isolated [42-43]. The first two receptors bind with high affinity the mammalian ligands NMB (BB₁ receptor) and GRP (BB₂ receptor), respectively, as well as bombesin and a number of the other peptides isolated primarily from the skin of various frogs (litorin, ranatensin, alytesin, etc) [42-43,229] and numerous synthetic analogues of Bn/GRP/NMB [87,249]. BB₃ is an orphan receptor, with a high degree of homology to the BB₁ and BB₂ receptors [44], but has an unknown natural ligand because it has low affinity for all naturally occurring bombesin-related peptides [87,129,249]. These receptors are widely distributed in mammals especially in the CNS and gastrointestinal tract and have numerous effects both physiologically and in pathologic processes including having an autocrine growth action on normal tissues and tumors; potent CNS effects (satiety, circadian rhythm, various behaviours): and potent effects in the immune, gastrointestinal, respiratory and urogenital systems [17,57,87,91-92,103,122,278]. It has been proposed that they may be important in a number of human disorders including growth of human cancers; as biomarkers for diseases such as non-small cell and small cell lung cancer; in regulating energy homeostasis and obesity; in various CNS diseases including memory loss, anxiety and behavior disorders, and in inflammatory disorders such as arthritis, uveitis and sepsis [27,57,87,91-92,103,122-124,180,182,201-202].

GRP

GRP is a 27-amino acid peptide that was isolated in 1978 from porcine nonantral gastric tissue [135] and was named for its ability to stimulate gastrin release. GRP differs from the frog tetradecapeptide, bombesin, in only one amino acid in its last 10 carboxyl-terminal residues, which is its biologically active end. For a number of years GRP was thought to be the mammalian equivalent of frog bombesin, however Xenopus laevis has been shown to produce a 29 amino acid peptide homologous to mammalian GRP, and the same frog has been shown to express different mRNAs to encode both bombesin and GRP [98,158,229]. A single human GRP-encoding gene has been described and is located on chromosome 18q21 [112,160,229]. Three different mRNA species are identified in humans generated through alternative splicing that encode precursors of slightly different chain lengths [5]. The gene comprises three exons and two introns and the second intron possesses the alternate donor site, which is used to produce the three mRNAs [216]. The human GRP mRNA encodes for a precursor of 148 amino acids that contains a signal sequence [230]. GRP_1-27 is formed by multiple enzymatic cleavages at both the amino terminus and the carboxyl terminal extended portion of the precursor. GRP_1-27 can be processed further to give GRP_10-27 [193] (which was originally termed neuromedin C) [145]. GRP is found widely, especially in the CNS and the gastrointestinal tract [86,103,113]. In the gastrointestinal tract it is found in nerve fibers and cell bodies, especially of the myenteric plexus as well as the submucosal plexus and in sympathetic prevertebral ganglia. The highest levels are found in gastric fundus, antrum and pylorus [188]. In the CNS GRP immunoreactivity is widespread in cell bodies of the cortex, pons, hypothalamus, nucleus of the solitary tract, superior olivary nucleus, nerve fibers in the thalamus, amydala, dorsal vagal nucleus and in the spinal sensory ganglia [4,86,103,152,254]. GRP has a wide range of actions, which will be briefly discussed below in the physiology and pathophysiology sections.

NMB

NMB is a decapeptide which was originally isolated from porcine spinal cord [144] and is the mammalian equivalent of the frog peptide ranatensin, to which it has an almost identical COOH terminus with six of seven amino acid identities [162]. The location of the human NMB gene is chromosome 15q11 [62,100]. NMB is encoded as a prepro-NMB, a 76 amino acid precursor that consists of a 24 amino acid signal peptide, NMB-32 and a 17 amino acid carboxyl terminal extension peptide [100]. The predicted amino acid sequence for NMB-32 is highly conserved in human, rat and pig with only differences of four amino acids [162,254]. The NMB gene is encoded in three exons and studies on rat and human genomic DNA are consistent with only a single NMB gene present. In the human Northern blot analysis reveals high expression in the hypothalamus, colon, stomach and low levels in the pancreas, cerebellum and adrenals [162]. By in situ hybridization studies NMB mRNA was found in rat brain in the greatest amounts in the olfactory bulb, dentate gyrus and dorsal root ganglion [254]. NMB has a wide range of physiological and pharmacological effects and these will be discussed later.

Bombesin Receptor Subtypes: General

In early binding/pharmacological and biological studies of bombesin-related peptides, bombesin or synthetic analogues of bombesin were almost invariably used as the agonist ligands and radiolabeled probes [87]. While some studies suggested that more than one receptor subtype might mediate the action of these peptides, it was not until 1989 that firm pharmacological and functional data convincingly demonstrated more than one subtype [87,252-253]. The failure to earlier demonstrate receptor subtypes occurred primarily because the affinity of bombesin and many of the synthetic analogues used is relatively high for both BB₁ and BB₂ receptors and very low for BB₃ receptors, making it difficult to distinguish these subtypes with these ligands [58,87,249]. In 1989, using subtype specific antagonists as well as selective agonists such as NMB and GRP [252-253], both BB₁ receptors and BB₂ receptors were shown to exist in rat tissues. Both were subsequently cloned [5,231,255], as was the BB₃ receptor [44,92].

BB₁ Receptor

The human BB₁ receptor [8,195,249], and the rat BB₁ receptor [9,106,114,206,252-253,258] have a greater than 100-fold higher affinity for NMB than GRP. In one recent study comparing both native and transfected human BB₁ receptors and human BB₂ receptors [249], NMB had >600-fold selectivity for the human BB₁ receptor over the human BB₂ receptor. Bombesin and the frog peptides ranatensin and litorin also have relatively high affinity for the BB₁ receptor [96,114,129,249,256], as does the synthetic bombesin analogue [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) [129,187,195,249]. The rat BB₁ receptor was cloned in 1991 [255], followed by the cloning of the human BB₁ receptor [25].

The human BB₁ receptor is a 390 amino acid protein and shows an 89% amino acid identity with the rat BB₁ receptor. It has 55% amino acid identities with the human BB₂ receptor and 47% with the human BB₃ receptor [87]. It was subsequently cloned from mouse [164], monkey [215] and the frog Bombina orientalis [157]. The human BB₁ receptor gene is at chromosome 6p21-pter and contains three exons and two introns [25,87,164,255]. The human BB₁ receptor has three potential N-linked glycosylation sites. The mature receptor is glycosylated having a molecular weight of 72 kDa and the deglycosylated receptor is 43 kDa [8]. Detailed studies in the rat BB₁ receptor demonstrate each potential N-linked glycosylation site is glycosylated with tri- and or tetra-antennary complex oligosaccharide chains and the mature receptor is a sialoprotein [101].

Expression levels have been reported in human, rat, mouse and monkey [25,87,164,255]. In the monkey [215] the highest levels of BB₁ receptor are in the testis and stomach as well as in the CNS including the amydala, caudate nucleus, hippocampus, hypothalamus, thalamus, brain stem and spinal cord. BB₁ receptors also occur on a large number of different tumors [113,195] including CNS tumors as well as tumors of the lung, ovary, pancreas and carcinoids [87].

There are few specific receptor antagonists for the BB₁ receptor [58,87]. The peptoid antagonist PD 168368 has the highest affinity and selectivity for the BB₁ receptor. PD 168368 has a high affinity (K_i 0.25-0.51 nM) for the BB₁ receptor from humans and rat (K_i 39 nM), a 2250-fold lower affinity for human BB₂ receptor and 33-fold lower affinity for the rat BB₂ receptor and a >20,000 fold lower affinity for the human BB₃ receptor [58,87,206,247].

BB₂ Receptor

The human BB₂ receptor [8,50,195,249], as well as the rat [96,106,114,252], mouse [6,80,206,246,248], and guinea pig BB₂ receptors [89,125] have a greater than 50-fold higher affinity for GRP than NMB. In a recent study [249] using both native human BB₂ receptor containing cells and BB₂/BB₁ receptor transfected cells, GRP had >2500 higher affinity for the human BB₂ receptor than the human BB₁ receptor. Bombesin and numerous frog peptides also have a high affinity for the BB₂ receptor [89,96,249], as do a number of synthetic bombesin analogues including [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) [129,187,195,249], which also has a high affinity for the BB₁ receptor [129,151,187] and human BB₃ receptor [129,151,187].

In 1990 the mouse BB₂ receptor was the first bombesin receptor to be cloned [5,231], closely followed by the cloning of the human BB₂ receptor [25]. The BB₂ receptor has now been cloned or partially characterized in 21 species [3]. The human BB₂ receptor is a 384 amino acid protein and shows a high degree of homology with the mouse receptor with 90% amino acid identities [25]. It has 55% amino acid identities with the human BB₁ receptor and 51% with the human BB₃ receptor [44,87]. The human BB₂ receptor has two sites for potential N-linked glycosylation and the mouse BB₂ receptor has four [5,25,231]. The mature murine BB₂ receptor is 82 kDa, the mature human BB₂ receptor is 60 kDa and the deglycosylated forms are 43 kDa [8,101]. For the murine BB₂ receptor, detailed serial deglycosylation studies as well as mutagenesis studies altering the N-linked glycosylation sites combined with receptor cross-linking studies and expression of the receptor in baculovirus have been carried out [7,101-102]. These studies demonstrate the murine BB₂ receptor is glycosylated at each of the four potential N-glycosylation sites with tri- or tetra-antennary complex oligosaccharide chains, the length of which various from 5-12 kD and that the receptor is not a sialoprotein, contains no O-linked glycosylation and the extent of the glycosylation affects receptor expression [7,102,157]. The human BB₂ receptor gene is located at Xp22 and contains three exons and two introns [25,131,266].

Expression levels of the BB₂ receptor have been reported in human, mouse and monkey [4-5,25,215,231]. In the monkey [215], where BB₂ receptor distribution has been studied in detail, the highest levels of the BB₂ receptor are in the pancreas, with lesser amounts in the stomach, prostate, skeletal muscle and CNS. In monkey CNS [215] BB₂ receptor mRNA is widely expressed with the highest amounts in the hippocampus, hypothalamus, amydala and pons. Detailed mapping studies are also reported in the rat brain, where BB₂ receptor mRNA is found in all regions, with the highest amount in the hypothalamus, particularly the suprachiasmatic and supraoptic nuclei as well as in the magnocellular preoptic nucleus in the basal ganglia and the nucleus of the lateral olfactory tract [4]. Mapping studies using a specific BB₂ receptor antibody confirmed widespread distribution in the rat brain, showing especially strong immunoreactivity in the nuclei of the amygdala and in the nucleus tractus solitarius [94].

BB₂ receptors are one of the most frequently over-expressed or ectopically expressed receptors on human cancers [27,90-92,175]. They have been widely studied and are frequently present in cancers of the lung, prostate, breast, head and neck, colon, uterus, CNS, ovary and kidney [90-92,175,195]. In various studies BB₂ receptors are present on 85-100% of small cell lung cancers, 74-78% of non-small cell lung cancers, 38-72% of breast cancers, 75% of pancreatic cancers, 62-100% of prostate cancers, 100% of head/neck squamous cell cancers, 85% of glioblastomas and 72% of neuroblastomas [90-91]. In many of these cancers they have an autocrine growth effect [30,90-92,111,185,225,259].

There are a number of different peptide and two nonpeptide receptor antagonist classes reported for the BB₂ receptor, some of which have high affinity and high selectivity for the BB₂ receptor [33,58,87-88]. They can be divided into twelve chemical classes of BB₂ receptor antagonists [58,87]. All classes are peptides or peptoid antagonists, except the two nonpeptide classes [33,58,87-88]. One nonpeptide class is composed of flavone derivatives (kuwanon G and H) isolated from extracts of the mulberry tree Morus bombycis [142] and the other two oxindole derivatives (CP-070,030,CP-75,998) [250]. Each of the classes of nonpeptide antagonists has low affinity (IC₅₀>1 µM) for the BB₂ receptor. These twelve classes include D-amino acid substituted substance P analogues; [D-Phe¹²]bombesin analogues; bombesin modified at position 13-14 or GRP modified at position 26-27; desMet¹⁴ or GRP²⁷ ester analogues; desMet¹⁴ or GRP²⁷ alkylamide analogues; [D-Pro¹³, ψ13-14 pseudo-bond] peptide analogues; D-amino acid substituted somatostatin analogues; cyclic bombesin peptide analogues; peptoids and finally the nonpeptide analogues, kuwanon G and H and CP-070,030/CP-75,998 [28,33,58,72,87-88,142,248,250,253,257].

BB₃ Receptor

Prior to the identification of the BB₃ receptor when it was cloned in 1992 from the guinea pig uterus [59], no pharmacological or functional data suggested its presence. The BB₃ receptor has now been cloned from rat [117], mouse [164], sheep [263], monkey [215] and human [44]. Each of these receptors, when expressed, have low affinity for the mammalian peptides GRP and NMB, and in the case of the human BB₃ receptor, it was shown to have low affinity for all known naturally occurring bombesin related peptides [117,124,129,206,208,249,265]. Therefore at present the natural ligand of this receptor is unknown.

The human BB₃ receptor is a 399 amino acid protein [44] and it shows 95% amino acid identities with the monkey [215] and 80% with the rat BB₃ receptor [87]. The human BB₃ receptor has 47% amino acid identities with the human BB₁ receptor and 51% with the human BB₂ receptor [44]. The human BB₃ receptor has a predicted molecular weight of 44.4 kDa and has two potential N-linked glycosylation sites, but there are no cross-linking studies of the mature BB₃ receptor.

The human BB₃ receptor gene is located at chromosome Xq25 and in the mouse at XA7.1-7.2 [44,60,262]. The human BB₃ receptor gene contains two introns and three exons [44,262].

Expression levels of the BB₃ receptor mRNA are reported in rat, sheep, mouse, monkey and guinea pig [39,44,59,84,117,215,250,263]. Detectable amounts are found in the monkey thyroid, pancreas and ovary [215]. Detailed studies show that BB₃ receptor mRNA is present in the islets in multiple species including human [45]. In the CNS BB₃ receptor mRNA is expressed in a more restricted distribution than BB₁ receptor or BB₂ receptor [39,84,117,215], although in a recent study it is more widely distributed [276]. In the rat and mouse [39,117,276] and in the monkey brain BB₃ receptor mRNA is present in the highest amounts in the hypothalamus [215,276] and is particularly high in the preoptic nucleus, the PVN, the dorsomedial hypothalmic nucleus and the arcuate nucleus, supporting the hypothesis that the BB₃ receptor may be important for the hypothalamic regulation of energy homeostasis [276]. In the monkey brain BB₃ receptor mRNA is present in the highest amounts, after the hypothalamus [215], in the pituitary gland, amygdala, hippocampus and caudate nucleus [215]. In the mouse and rat brains [276], no BB₃ receptor mRNA can be detected in the cerebral cortex, olfactory bulb, hippocampal formation, cerebellum, substantia nigra or ventral tegmental area. In rat and mouse brains [276], double in situ hydridization studies show that BB₃ receptor mRNA colocalizes frequently with glutamatergic neurons, and to a lesser extent with cholinergic or GABAergic neurons, and CRF or GHRH, but not with NPY, POMC, orexin/hypocretin, MCH,GnRH or kisspentin. Specific BB₃ receptor antibodies have been used to localise the receptor in the tunica muscularis of the gastrointestinal tract [186] and in the rat CNS [84]. In the gastrointestinal tract the BB₃ receptor was detected in myenteric and submucosal ganglia as well as the interstitial cells of Cajal [186]. In the CNS particularly strong staining was detected in the cerebral cortex, hippocampus, hypothalamus and thalamus [186].

The natural ligand for the BB₃ receptor remains unknown. Recently two Drosphilia G-protein coupled receptors (CG30106,CG14593) have been identified and belong to the BB₃ receptor family [69,74,81]. These receptors interact with two ligands CCHamide-1[SCLEYGHSCWGAH-NH₂] and CCHamide-2[GCQAYGHVCYGGH-NH₂], which when administered to blowflies increased feeding [81]. Unfortunately, neither of the CCHamide peptides activated the BB₃ receptor[81] and each was found to have a very low affinity for the human BB₃ receptor (Jensen, unpublished data). Using a bacterial two-hybrid system, the BB₃ receptor was found to interact with a novel 354 amino acid protein, named bombesin receptor activated protein (BRAP) [115]. BRAP is found in both the cellular cytoplasm and nucleus, its expression promotes G1 to S phase transition, accelerates DNA snythesis, and promotes the proliferation of bronchial epithelial cells [115]. This has led to the proposal that BRAP may be important in BB₃ receptor mediated changes in cell cycle regulation and in wound healing in bronchial epithelial cells [115]. Overexpression of BRAP [191] in bronchial epithelial cells inhibits the ability of these cells to take up antigen suggesting it may play an important role in the antigen presenting process of bronchial epithelium.

Even although no high affinity natural ligands exist for this receptor it has been found that the synthetic bombesin ligand, [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) binds and activates both cells containing the natural occurring [208] and expressed BB₃ receptors with high affinity/potency [129,187,206-207,249]. When the rat BB₃ receptor was cloned [117] it was surprisingly found that [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) had low affinity for this receptor, whereas it had high affinity for the monkey BB₃ receptor, similar to the human receptor [215]. Using a chimeric receptor approach [117] in which the individual extracellular loops of the rat BB₃ receptor were replaced with the corresponding human sequences the important residues were localised to the 4^th extracellular domain (1^st=N-terminus). Within this region, using site-directed mutagenesis [117], the mutation of Y²⁹⁸E²⁹⁹S³³⁰ (rat) to S²⁹⁸Q²⁹⁹T³⁰⁰ (human) or of D³⁰⁶V³⁰⁷H³⁰⁸ (rat) to A³⁰⁶M³⁰⁷H³⁰⁸ (human) partially mimic the effect of switching the entire 4^th extracellular domain. These results indicate that variations in the 4^th extracellular domains of the rat and human BB₃ receptor are responsible for the differences in affinity for [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin_6-14 [117].Subsequent studies demonstrated the synthetic bombesin analogue, [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin_6-14, in addition to having high affinity for monkey and human BB₃ receptors, also had high affinity for all BB₁ and all BB₂ receptors, as well as a frog BB₄ subtype which is not found in mammals [129,154,187,206-208,249]. Due to the lack of selectivity of the high affinity agonist, [D-Phe⁶,β-Ala¹¹,Phe¹³, Nle¹⁴]bombesin_6-14 for the human BB₃ receptor, a number of groups have attempted to develop more selective BB₃ receptor ligands. In one study [127] rational peptide design was used by substituting conformationally restricted amino acids and a number of BB₃ receptor selective agonists were identified with two peptides with either an (R) or (S)-amino-3-phenylpropionic acid substitution for β-Ala¹¹ in the prototype ligand having the highest selectivity (i.e.17-19-fold) [127]. Molecular modeling demonstrated these two selective BB₃ receptor ligands had a unique conformation of the position of the 11 β-amino acids, which likely accounted for their selectivity [127]. In a second study [126] two strategies were used to attempt to develop a more selective BB₃ receptor ligand: substitutions on the phenyl ring of Ala¹¹ and the substitution of additional conformationally restricted amino acids into the position 11 of [D-Phe⁶,β-Apa¹¹,Phe¹³,Nle¹⁴]bombesin_6-14 or its D-Tyr⁶ analogue. One analogue, [D-Tyr⁶,Apa-4Cl¹¹,Phe¹³,Nle¹⁴]bombesin_6-14 retained high affinity for BB₃ receptor and was 227-fold selective for the BB₃ receptor over the human BB₂ receptor and 800-fold selective over the human BB₁ receptor [126]. Using [D-Phe⁶,β-Ala,sup>11,Phe¹³,Nle¹⁴]bombesin_6-14 or its D-Tyr⁶ analogue as the prototype, three studies [15,260-261] reported shortened analogues with selectivity for BB₃ receptor assessed by calcium or FIPR calcium assays. A recent study has assessed the selectivity of four of the most selective of these shortened [D-Phe⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) analogues by binding assays as well as assessment of phospholipase C potencies [128]. Only the novel compound Ac-Phe,Trp,Ala,His(tBzl),Nip,Gly,Arg-NH₂ (compound 34 in reference [15]) had a 14-fold higher affinity for BB₃ receptor than BB₁ receptor and >20 fold for BB₂ receptor [128], however it was less BB₃ receptor selective than [D-Tyr⁶,Apa-4Cl¹¹,Phe¹³,Nle¹⁴] bombesin_6-14 (i.e. >100 fold selectivity) [126,128].

Recently a number of BB₃ receptor nonpeptide agonists have been described including derivatives of omeprazole [20], benzodiazepine sulfonamide analogues [24], derivatives of an analogue found to have activity during high throughput screening [7-benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]- [2,7]naphthyridin-1-ylamine] [66-67], substituted biphenyl imidazole analogues [70], 2-biarylethylimidazole analogues [116], pyridinesulfonylureas and pyridinesulfonamide analogues [120]. Of these the selective nonpeptide high affinity agonist, MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-[[1-(trifluoromethyl)cyclopropyl] methyl]-1H-imidazol-2-yl)propan-2-ol ] [37-39], or Bag-1, (2-(4-[2-[5-(2,2-dimethylbutyl)-1H-imidazol-2-yl] ethyl]phenyl) pyridine (compound 9 in [116]) have been the most widely used for agonist studies of the BB₃ receptor. Also a high affinity selective BB₃ receptor peptide antagonist, Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate] has been described [45,64] MK-5046 is orally active and shown to be active in dog, mice, rat, monkey and human [65,194]. In a recent comparison of their selectivity for human BB₃ receptor cells expressing native or transfected receptors, MK-50946 and Bantag-1 were found to have high affinity for the human BB₃ receptor (17.7-18.8, 1-1.6 nM, resectively) and to be 555-fold and 6250-fold selective, respectively, based on affinities for the human BB₃ receptor over either the human BB₁ or BB₂ receptor. In terms of selectivity for activation of the human BB₃ receptor (phospholipase C activation), MK-5046 had a selective potency of >10,000-fold over the human BB₁ and human BB₂ receptors [155]. A number of studies using site-directed mutageneis have examined the molecular basis for agonist activation and selectivity for the human BB₃ receptor [54,56,249]. In one study [54] epitopes determining the agonist property of [D-Tyr⁶,(R)-Apa-Cl¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) or Ac-Phe,Trp,Ala,His(tBzl),Nip,Gly,Arg-NH₂ (compound 34 in reference [15]) were examined. The mutational map for Ac-Phe,Trp,Ala,His(ψBzl),Nip,Gly,Arg-NH₂ spanned the entire binding pocket, whereas that for [D-Tyr⁶,(R)-Apa-Cl¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) was confined to the center of the pocket encompassing the opposing faces of the extracelluar segment of TM-111,TM-V1 and TM-VIII [54]. Using a chimeric receptor approach combined with site-directed mutagenesis [56], the selectivity of [D-Tyr⁶,(R)-Apa-Cl¹¹,Phe¹³,Nle¹⁴]bombesin(6-14), Ac-Phe,Trp,Ala,His(ψBzl),Nip,Gly,Arg-NH₂, and [D-Tyr⁶,(R)-Apa¹¹,Phe¹³,Nle¹⁴]bombesin(6-14) for the human BB₃ receptor was examined. Even though these three human BB₃ receptor agonists were developed from the same template peptide, [D-Tyr⁶,β-Ala¹¹,Phe¹³,Nle¹⁴]bombesin(6-14), their molecular determinants of selectivity/high affinity varied considerably [56].

Physiological and pathophysiological roles

A very wide range of effects have been reported with bombesin related peptides [57,90-92,103,122-124,229,278], but because of the use of nonselective ligands and lack of selective antagonists until recently, the bombesin receptor subtype mediating these effects, as well as which effects were pharmacological and which were physiological, were largely unknown [87]. Recent studies using mice with a specific receptor knockout, as well as studies using selective ligands and molecular studies have provided more detailed information on the subtypes involved [57,87,91-92,103,122-124,229].

BB₁: Physiological and pathophysiological roles

Specific binding studies, as well as receptor antagonist and BB₁ receptor knockout studies, provide evidence that BB₁ receptor activation can stimulate contraction of urogenital and gastrointestinal smooth muscle (esophageal, gastric, colonic, gallbladder) [10,92,97,143,174,204,223,252-253]; potently inhibit thyrotropin release acting as an autocrine/paracrine regulator [168,172,177-179] [92,167]; have potent CNS effects including inhibiting food intake independent of BB₂ receptor stimulation and energy metabolism [78,92,103,108-110,140,176]; thermoregulation [163]; mediate aspects of the stress response, fear response [18]; various behaviours such as spontaneous activity [18,138-139,270-271]; in pain and itch sensation [47,146]; scratching behavior [235]; and is important in memory and learning [270]. The BB₁ receptor is frequently over-expressed by various tumors [91-92,113,175,214,236] including 55% of small cell lung cancers, 67% of non-small cell lung cancers, 46% of intestinal carcinoids, 86% of ovarian cancers as well [91-92,113,133,150,195,214]. NMB has been shown to function as an autocrine growth factor in non-small cell lung cancer, small cell lung cancer cells, and in colon cancer [19,91-92,133,148,214,226]. No specific diseases have been proven to be associated with alterations in the BB₁ receptor at present, but studies show that conditions with increased TSH release such as hypothyroidism are associated with decreased pituitary NMB levels [93,173], while in hyperthyroidism where the TSH levels are suppressed, there is an increased pituitary NMB level [93,172] suggesting NMB could play and important role in human thyroid disorders. It has been proposed that alterations in the neuromedin B gene (particularly a p.P73T missense mutation in the NMB beta gene or a NMB rs3809508 polymorphism) may be associated with eating disorders and susceptabilty to obesity energy intake [11,14,184,232].

BB₂: Physiological and pathophysiological roles

Binding studies as well as results from BB₂ receptor agonist and antagonist studies and BB₂ receptor knockout studies provide evidence that BB₂ receptor activation is involved in a wide range of physiological functions [17,57,86-87,91-92,103,113,122]. In the gastrointestinal tract BB₂ receptor activation causes stimulation of acid secretion, as well as pancreatic and intestinal secretion [17,86-87,92,113,220,251] and stimulates gastrointestinal motility causing gallbladder contraction, as well as affecting antral and intestinal motility and intestinal reflexes [17,86,92,113]. GRP plays an essential role in the intestinal peristaltic reflex because it is a modulatory neurotransmitter of the descending phase of the peristaltic reflex [63]. In humans GRP infusions and the use of a specific BB₂ receptor antagonist demonstrated BB₂ receptor activation causes gallbladder contraction, stimulates gastric acid, biliary and pancreatic secretion, slows gastric emptying and slows small bowel transit [37,75,92,113]. In addition to stimulating tissues directly by interacting with BB₂ receptors, GRP stimulates the release of a large number of hormones and neurotransmitters (cholecystokinin, gastrin, somatostatin, pancreatic glucagon, insulin, enteroglucagon, neurotensin, gastric inhibitory polypeptide) which can also have potent effects [12,17,55,86,92,113,134,264]. In addition to these endocrine effects, BB₂ receptor knockout studies as well as direct stimulation studies demonstrate GRP interaction with BB₂ receptors contributes to insulin secretion by activation of autonomic nerves at the ganglionic level as well as by direct effects on the islet [1,61,73,95,181]. Activation of the BB₂ receptor in immune cells also causes a diverse number of important responses including stimulating natural killer and antibody-dependent cellular cytoxicity in leukocytes [35,38,136], chemotaxis of lymphocytes [137] and neutrophils [31], modulation of phagocytic function in macrophages [34] and chemoattractant effects in monocytes [205]. BB₂ receptors are reported to be important for fetal lung development including lung branching and differentiation as well as a number of lung diseases, especially bronchopulmonary dysplasia [29,36,53,92,240]. BB₂ receptors has have been extensively studied for their effects on satiety using both pharmacologic studies and BB₂ receptor knockout mice [48,68,92,105,107,110,140]. These effects are not inhibited by capsaicin treatment demonstrating they are either mediated by capsaicin independent pathways or involve direct activation of BB₂ receptor in the CNS [107]. Numerous studies demonstrate that BB₂ receptors play a number of important roles in various processes in the CNS including regulation of circadian rhythm, body temperature control, grooming behaviours, modulation of fear, stress and anxiety, memory and CNS effects on gastrointestinal function including acid secretion [17,49,52,87,92,103,139,152,198-203,212,268-269]. The role of BB₂ receptor activation has been studied extensively in the growth of normal and neoplastic tissues [87,113,149,175]. This widespread interest occurred after BB₂ receptor activation on human small cell lung cancer cells not only resulted in growth of the tumor cells, but bombesin-like peptides were secreted by the tumor and thus it appeared to be acting as an autocrine growth factor [30,89,91-92]. Subsequent studies demonstrated such an autocrine growth effect in a large number of tumors including neuroblastomas, squamous head and neck tumors, pancreatic cancer cells, colon cancer, prostate cancer, glioblastoma cells and non-small cell lung cancer cells [90-92,113]. Furthermore, many human cancers over-express or ectopically express BB₂ receptor [90-92,113,175,195]. The effects of BB₂ receptor activation on different tumors may differ because detailed studies on colon cancer demonstrate the BB₂ receptor has a morphogenic effect rather than a mitogenic effect [21-22,85]. BB₂ receptors have been proposed to be important in the mediation of a number of human disorders including disorders of lung development such as bronchopulmonary dysplasia, various lung disorders, and the growth and differentiation of human cancers [87,113]. Recent studies suggest BB₂ receptors may be particularly important in mediating male penile responses as well as pruritic responses [2,209-213,237]. A sexually dimorphic BB₂ receptor system has been described in the spinal cord that is essential for regulating male sexual function including penile reflexes and ejaculation [209-213]. This system is affected adversely by stress and this raises the possibility it could be important in various psychogenic related erectile dysfunctions [212]. In BB₂ receptor knockout mice reduced pruritogenic responses are found, whereas responses to other stimuli are intact (thermal, inflammatory, pain) [237]. Furthermore, pruritis in wild type mice is blocked by intrathecal adminstration of a BB₂ receptor antagonist [237]. Selective ablation of BB₂ receptor neurons in the spinal cord of mice results in scratching deficits in response to pruritic stimuli, but not to pain stimuli [238]. Additional studies provide evidence that glutamate acts as the neurotransmitter for BB₂ receptor-sensitive and -insensitive itch synaptic transmission in mammalian spinal cord [99]; that MrgprA3-expressing neurons co-expressing GRP and MRgprC11 are important in mediating chloroquine-induced itching [118] and that the mu-opioid receptor (MOR) isoform, MOR1D can heterodimerize with the BB₂ receptor in the spinal cord to mediate itching responses [119]. These studies suggest that BB₂ receptors are important mediators of the itching sensation in the spinal cord [83,238,241].

BB₂ receptors are one of the most frequently and widely over-expressed or ectopically expressed G protein-coupled receptors in human tumors including prostate, small cell lung cancers, non-small cell lung cancers, breast cancer, pancreatic cancer cell line, head and neck squamous cell cancers and neuroblastomas/glioblastomas [87,90-92,113,175,214]. This over-expression as well as the autocrine growth effects on many tumors is playing a potential role in a number of aspects of the treatment and management of these tumors [90-92,214]. These include efforts to inhibit the autocrine effects as well as using the BB₂ receptor as targets to image the tumor as well as targets to deliver cytotoxic treatment selectively to the tumor [16,23,27,90-92,113,151,166,214,217-218,227,274-275]. Because GRP or it precursors are frequently synthesized as well as secreted by small cell lung cancers, their serum levels have been assessed in relationship to disease stage and activity, and assessment of ProGRP serum levels has been shown to play a useful role in both the diagnose and treatment of small cell lung cancers [76,161,170-171,233,239,242,273]. Because of its widespread participation in so many processes it has been proposed that the BB₂ receptor could be a therapeutic target in a number of disorders. These include: as a target in CNS disorders [18,138,198-202] including psychiatric disorders (anxiety, bipolar disorder, fear related disorders, schizophrenia, autism, cognitive disorders) as well as neurological disorders (neuroprotective effect during stroke, memory disorders, treatment of brain tumors [neuroblastomas, gliomas]); as a possible target in patients with psychogenic erectile dysfunction [202,212]; human pruritic disorders [83,147,237-238,241]; in a variety inflammatory disorders [182] such as many inflammatory lung diseases (chronic obstructive lung disease, response to tobacco smoke), rheumatoid arthritis, sepsis, uveitis, inflammatory bowel disorders [26,32,169,182-183]; lung disorders such as bronchopulmonary dysplasia [36,190]; for antitumor treatment of various BB₂ receptor containing neoplasms by the use of BB₂ receptor antagonists, frequently combined with other cytotoxic agents or by the use of BB₂ receptor specific ligands that interact with the tumoral BB₂ receptor and inhibit tumoral growth due to their attachment to cytotoxic agents (doxorubicin, camptothecin derivatives) or the attached radiolabels[40,91-92,166,197,214,217,274,277]; for the treatment of prostatic hyperplasia as well as prostatic cancer [184] [40,196,214,219,228,267]; as tumor markers (especially in lung cancer) [185-188] [76,161,170,273] and the use of radiolabeled bombesin analogues to image tumors (prostate, lung, breast) [91-92,189,214,275].

A translocation on chromosome X (the BB₂ receptor gene is at Xp22) 46,X,t(X;8)(p22.13;q22) which disrupts the BB₂ receptor gene is reported in an individual with autism and multiple exostoses, mental retardation and epilepsy [13,82]. This raises the possibility that the BB₂ receptor gene could be a candidate for causing Rett syndrome, however no alterations in the BB₂ receptor gene were found in 25 unrelated Rett patients [71]. Studies carried out in other countries have not found a major role of the BB₂ receptor gene in autism disorders [130,156]. The possibility that alterations in the BB₂ receptor gene could be important in panic disorder has also been investigated in two studies, with a weak association (p=0.02) found in one study [77], and the other reporting no association [234].

BB₃: Physiological and pathophysiological roles

Because the natural ligand of the BB₃ receptor is not known and because, until only recently there was no good antagonist or selective agonist for this receptor, most of the information on the possible physiological or pathophysiological role of this receptor has come from BB₃ receptor knockout studies [57,87,123-124]. In the initial study of BB₃ receptor knockout mice [165] they developed mild obesity, associated with hypertension and impairment of glucose metabolism. These changes were associated with increased feeding behaviour, reduced metabolic rate increased serum leptin and hyperphagia [165]. These results suggested the BB₃ receptor could play a role in energy balance, weight control and control of blood glucose levels [165]. Subsequent studies of BB₃ receptor knockout mice showed they had altered taste preferences [272], perhaps contributing to increased feeding. BB₃ receptors are found on normal islets [46] and BB₃ receptor knockout mice have increased insulin levels [132] due to dysregulation of insulin control as well as altered glucose metabolism mainly due to impaired GLUT4 translocation in adipocytes [159].

The BB₃ receptor in a double-labeled in situ hybridization study [51] was found to be expressed in CNS orexin neurons as well as many cells around these neurons. In functional studies [51] BB₃ receptor agonists increase cytosolic calcium in these orexin neurons and hyperpolarize the neurons. In the presence of GABA receptor blockers, the a BB₃ receptor agonist caused depolarization and increased firing frequency of the orexin neurons [51], leading to the conclusion that in the CNS, BB₃ `receptor activation indirectly inhibits orexin neurons through GABAergic input as well as directly activating orexin neurons. It was proposed this pathway might serve as a novel target for the treatment of obesity [51]. In BB₃ receptor knockout mice the hyperphagia response to melanin-concentrating hormone (MCH) is impaired [121] with increased MCH receptor levels in the hypothalamus suggesting this may contribute to the hyperphagia. A detailed study of factors contributing to obesity in BB₃ receptor knockout mice [104] demonstrated that hyperphagia is a major factor leading to their increased body weight and hyperinsulinemia. However, a pair feeding study of BB₃ receptor knockout mice [104] did not completely normalize fat distribution and plasma leptin levels suggesting there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype[104]. BB₃ receptor knockout studies also suggest BB₃ receptor is important in various behavioral effects such as those regulating social isolation [268] or modulating anxiety [269]. MK-5046, the recently described high affinity BB₃ receptor agonist which is orally active, and highly selective for the BB₃ receptor [65,194,222], or Bag-1, [45,116], have been used in a number of in vivo studies providing support for a number of the findings from the BB₃ receptor knockout mice studies. Using the selective BB₃ receptor nonpeptide agonist (Bag-1) and the BB₃ receptor peptide antagonist (Bantag-1), the BB₃ receptor, in multiple species, is found to be important in regulating glucose-stimulated insulin secretion, raising the possibility that it may have a role in the treatment of diabetes mellitus [45]. In another study [65] single doses of the BB₃ receptor agonist, MK-5046 inhibited food intake and increased fasting metabolic rate in wild type, by not BB₃ receptor knockout mice [65]. Furthermore, treatment for two weeks with MK-5046 [65] reduces body weight in mice and rats, causing modest increases in body temperature, heart rate and blood pressure. In dogs MK-5046 treatment results in persistent weight loss, accompanied by increases in body temperature and heart rate [65]. These results show an anti-obesity effect of MK-5046 in rodents and dogs and support the possible use of BB₃ receptor agonism as an approach to the treatment of obesity [64-65]. These studies as well as others [141], demonstrate that BB₃ receptor activation can regulate body temperature, similar to effects previously described for the BB₂ receptor [87].

Recent studies show BB₃ receptors are expressed in developing and fetal lungs [41,224] and are up-regulated in response to injury [190,243-244]. The BB₃ receptor is reported to occur in skeletal muscle [192] and to be down regulated in skeketal muscle cells or myoctes from obese subjects or patients with diabetes mellitus. Furthermore, differences in the effects of a BB₃ receptor agonist on skeletal muscle cells/myocytes [192] from normal, obese, and diabetic subjects in GLUT4 extent, location, and glucose transport have been reported, leading to the proposal that these alterations in BB₃ receptor expression/responsiveness in skeletal muscle cells could be important in the metabolic response to obesity/diabetes mellitus [192]. Although the function of BB₃ receptor in the gastrointestinal tract is largely unknown, BB₃ receptor have been detected in myenteric and submucosal plexi as well as the interstitial cells of Cajal, leading the authors to propose that the BB₃ receptor is likely involved in the regulation of gastrointestinal motility [186]. Lastly, BB₃ receptors are ectopically or over-expressed in a number of human tumors [44,113,195,221,236,245] and activation of the BB₃ receptor has been shown to increase MAP kinase activation, nuclear oncogene expression and adhesion of lung cancer tumor cells which is proposed to contribute to increased tumor invasion by these tumors [79]. BB₃ receptor activation in lung cancer cells [153] stimulates their growth as a result of EGF receptor transactivation and the transactivation is mediated by activation of Src family kinases and generation of reactive oxygen species.

1. Ahrén B. (2006) The insulin response to gastric glucose is reduced in PAC1 and GRP receptor gene deleted mice. Nutr Metab Cardiovasc Dis, 16 Suppl 1: S17-21. [PMID:16530124]

2. Akiyama T, Tominaga M, Davoodi A, Nagamine M, Blansit K, Horwitz A, Carstens MI, Carstens E. (2013) Roles for substance P and gastrin-releasing peptide as neurotransmitters released by primary afferent pruriceptors. J Neurophysiol, 109 (3): 742-8. [PMID:23155177]

3. Baldwin GS, Patel O, Shulkes A. (2007) Phylogenetic analysis of the sequences of gastrin-releasing peptide and its receptors: biological implications. Regul Pept, 143 (1-3): 1-14. [PMID:17395282]

4. Battey J, Wada E. (1991) Two distinct receptor subtypes for mammalian bombesin-like peptides. Trends Neurosci, 14 (12): 524-8. [PMID:1726343]

5. Battey JF, Way JM, Corjay MH, Shapira H, Kusano K, Harkins R, Wu JM, Slattery T, Mann E, Feldman RI. (1991) Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc Natl Acad Sci USA, 88 (2): 395-9. [PMID:1671171]

6. Benya RV, Fathi Z, Kusui T, Pradhan T, Battey JF, Jensen RT. (1994) Gastrin-releasing peptide receptor-induced internalization, down-regulation, desensitization, and growth: possible role for cyclic AMP. Mol Pharmacol, 46 (2): 235-45. [PMID:8078487]

7. Benya RV, Kusui T, Katsuno T, Tsuda T, Mantey SA, Battey JF, Jensen RT. (2000) Glycosylation of the gastrin-releasing peptide receptor and its effect on expression, G protein coupling, and receptor modulatory processes. Mol Pharmacol, 58 (6): 1490-501. [PMID:11093789]

8. Benya RV, Kusui T, Pradhan TK, Battey JF, Jensen RT. (1995) Expression and characterization of cloned human bombesin receptors. Mol Pharmacol, 47 (1): 10-20. [PMID:7838118]

9. Benya RV, Wada E, Battey JF, Fathi Z, Wang LH, Mantey SA, Coy DH, Jensen RT. (1992) Neuromedin B receptors retain functional expression when transfected into BALB 3T3 fibroblasts: analysis of binding, kinetics, stoichiometry, modulation by guanine nucleotide-binding proteins, and signal transduction and comparison with natively expressed receptors. Mol Pharmacol, 42 (6): 1058-68. [PMID:1336112]

10. Bitar KN, Zhu XX. (1993) Expression of bombesin-receptor subtypes and their differential regulation of colonic smooth muscle contraction. Gastroenterology, 105 (6): 1672-80. [PMID:8253343]

11. Blanchet R, Lemieux S, Couture P, Bouchard L, Vohl MC, Pérusse L. (2011) Effects of neuromedin-β on caloric compensation, eating behaviours and habitual food intake. Appetite, 57 (1): 21-7. [PMID:21527296]

12. Bloom SR, Edwards AV, Ghatei MA. (1983) Endocrine responses to exogenous bombesin and gastrin releasing peptide in conscious calves. J Physiol (Lond.), 344: 37-48. [PMID:6361234]

13. Bolton P, Powell J, Rutter M, Buckle V, Yates JR, Ishikawa-Brush Y, Monaco AP. (1995) Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1). Psychiatr Genet, 5 (2): 51-5. [PMID:7551962]

14. Bouchard L, Drapeau V, Provencher V, Lemieux S, Chagnon Y, Rice T, Rao DC, Vohl MC, Tremblay A, Bouchard C et al.. (2004) Neuromedin beta: a strong candidate gene linking eating behaviors and susceptibility to obesity. Am J Clin Nutr, 80 (6): 1478-86. [PMID:15585758]

15. Boyle RG, Humphries J, Mitchell T, Showell GA, Apaya R, Iijima H, Shimada H, Arai T, Ueno H, Usui Y et al.. (2005) The design of a new potent and selective ligand for the orphan bombesin receptor subtype 3 (BRS3). J Pept Sci, 11 (3): 136-41. [PMID:15635635]

16. Breeman WA, De Jong M, Bernard BF, Kwekkeboom DJ, Srinivasan A, van der Pluijm ME, Hofland LJ, Visser TJ, Krenning EP. (1999) Pre-clinical evaluation of [(111)In-DTPA-Pro(1), Tyr(4)]bombesin, a new radioligand for bombesin-receptor scintigraphy. Int J Cancer, 83 (5): 657-63. [PMID:10521803]

17. Bunnett NW. (1994) Gastrin-releasing peptide. In Gut Peptides Edited by Walsh JH, Dockray GJ (Raven Press) 423-445. [ISBN:0781701155]

18. Bédard T, Mountney C, Kent P, Anisman H, Merali Z. (2007) Role of gastrin-releasing peptide and neuromedin B in anxiety and fear-related behavior. Behav Brain Res, 179 (1): 133-40. [PMID:17335915]

19. Cardona C, Rabbitts PH, Spindel ER, Ghatei MA, Bleehen NM, Bloom SR, Reeve JG. (1991) Production of neuromedin B and neuromedin B gene expression in human lung tumor cell lines. Cancer Res, 51 (19): 5205-11. [PMID:1717141]

20. Carlton DL, Collin-Smith LJ, Daniels AJ, Deaton DN, Goetz AS, Laudeman CP, Littleton TR, Musso DL, Morgan RJ, Szewczyk JR et al.. (2008) Discovery of small molecule agonists for the bombesin receptor subtype 3 (BRS-3) based on an omeprazole lead. Bioorg Med Chem Lett, 18 (20): 5451-5. [PMID:18818070]

21. Carroll RE, Matkowskyj KA, Chakrabarti S, McDonald TJ, Benya RV. (1999) Aberrant expression of gastrin-releasing peptide and its receptor by well-differentiated colon cancers in humans. Am J Physiol, 276 (3): G655-65. [PMID:10070042]

22. Carroll RE, Matkowskyj KA, Tretiakova MS, Battey JF, Benya RV. (2000) Gastrin-releasing peptide is a mitogen and a morphogen in murine colon cancer. Cell Growth Differ, 11 (7): 385-93. [PMID:10939592]

23. Chaudhry A, Carrasquillo JA, Avis IL, Shuke N, Reynolds JC, Bartholomew R, Larson SM, Cuttitta F, Johnson BE, Mulshine JL. (1999) Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer. Clin Cancer Res, 5 (11): 3385-93. [PMID:10589749]

24. Chobanian HR, Guo Y, Liu P, Lanza Jr TJ, Chioda M, Chang L, Kelly TM, Kan Y, Palyha O, Guan XM et al.. (2012) The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization. Bioorg Med Chem, 20 (9): 2845-9. [PMID:22494842]

25. Corjay MH, Dobrzanski DJ, Way JM, Viallet J, Shapira H, Worland P, Sausville EA, Battey JF. (1991) Two distinct bombesin receptor subtypes are expressed and functional in human lung carcinoma cells. J Biol Chem, 266 (28): 18771-9. [PMID:1655761]

26. Cornelio DB, Dal-Pizzol F, Roesler R, Schwartsmann G. (2007) Targeting the bombesin/gastrin-releasing peptide receptor to treat sepsis. Recent Pat Antiinfect Drug Discov, 2 (3): 178-81. [PMID:18221174]

27. Cornelio DB, Roesler R, Schwartsmann G. (2007) Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy. Ann Oncol, 18 (9): 1457-66. [PMID:17351255]

28. Coy DH, Heinz-Erian P, Jiang NY, Sasaki Y, Taylor J, Moreau JP, Wolfrey WT, Gardner JD, Jensen RT. (1988) Probing peptide backbone function in bombesin. A reduced peptide bond analogue with potent and specific receptor antagonist activity. J Biol Chem, 263 (11): 5056-60. [PMID:2451661]

29. Cullen A, Emanuel RL, Torday JS, Asokananthan N, Sikorski KA, Sunday ME. (2000) Bombesin-like peptide and receptors in lung injury models: diverse gene expression, similar function. Peptides, 21 (11): 1627-38. [PMID:11090916]

30. Cuttitta F, Carney DN, Mulshine J, Moody TW, Fedorko J, Fischler A, Minna JD. (1985) Autocrine growth factors in human small cell lung cancer. Cancer Surv, 4 (4): 707-27. [PMID:2445479]

31. Czepielewski RS, Porto BN, Rizzo LB, Roesler R, Abujamra AL, Pinto LG, Schwartsmann G, Cunha Fde Q, Bonorino C. (2012) Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils. Proc Natl Acad Sci USA, 109 (2): 547-52. [PMID:22203955]

32. Damin DC, Santos FS, Heck R, Rosito MA, Meurer L, Kliemann LM, Roesler R, Schwartsmann G. (2010) Effects of the gastrin-releasing peptide antagonist RC-3095 in a rat model of ulcerative colitis. Dig Dis Sci, 55 (8): 2203-10. [PMID:19894117]

33. de Castiglione R, Gozzini L. (1996) Bombesin receptor antagonists. Crit Rev Oncol Hematol, 24 (2): 117-51. [PMID:8889369]

34. De la Fuente M, Del Rio M, Ferrandez MD, Hernanz A. (1991) Modulation of phagocytic function in murine peritoneal macrophages by bombesin, gastrin-releasing peptide and neuromedin C. Immunology, 73 (2): 205-11. [PMID:1649124]

35. De la Fuente M, Del Rio M, Hernanz A. (1993) Stimulation of natural killer and antibody-dependent cellular cytotoxicity activities in mouse leukocytes by bombesin, gastrin-releasing peptide and neuromedin C: involvement of cyclic AMP, inositol 1,4,5-trisphosphate and protein kinase C. J Neuroimmunol, 48 (2): 143-50. [PMID:8227312]

36. Degan S, Lopez GY, Kevill K, Sunday ME. (2008) Gastrin-releasing peptide, immune responses, and lung disease. Ann N Y Acad Sci, 1144: 136-47. [PMID:19076373]

37. Degen LP, Peng F, Collet A, Rossi L, Ketterer S, Serrano Y, Larsen F, Beglinger C, Hildebrand P. (2001) Blockade of GRP receptors inhibits gastric emptying and gallbladder contraction but accelerates small intestinal transit. Gastroenterology, 120 (2): 361-8. [PMID:11159876]

38. Del Rio M, De la Fuente M. (1995) Stimulation of natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) activities in murine leukocytes by bombesin-related peptides requires the presence of adherent cells. Regul Pept, 60 (2-3): 159-66. [PMID:8746542]

39. DeMichele MA, Davis AL, Hunt JD, Landreneau RJ, Siegfried JM. (1994) Expression of mRNA for three bombesin receptor subtypes in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 11 (1): 66-74. [PMID:8018339]

40. Dumont RA, Tamma M, Braun F, Borkowski S, Reubi JC, Maecke H, Weber WA, Mansi R. (2013) Targeted radiotherapy of prostate cancer with a gastrin-releasing Peptide receptor antagonist is effective as monotherapy and in combination with rapamycin. J Nucl Med, 54 (5): 762-9. [PMID:23492884]

41. Emanuel RL, Torday JS, Mu Q, Asokananthan N, Sikorski KA, Sunday ME. (1999) Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation. Am J Physiol, 277 (5): L1003-17. [PMID:10564187]

42. Erspamer V. (1988) Discovery, isolation, and characterization of bombesin-like peptides. Ann N Y Acad Sci, 547: 3-9. [PMID:3071223]

43. Erspamer V, Melchiorri P, Erspamer CF, Negri L. (1978) Polypeptides of the amphibian skin active on the gut and their mammalian counterparts. Adv Exp Med Biol, 106: 51-64. [PMID:362860]

44. Fathi Z, Corjay MH, Shapira H, Wada E, Benya R, Jensen R, Viallet J, Sausville EA, Battey JF. (1993) BRS-3: a novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J Biol Chem, 268 (8): 5979-84. [PMID:8383682]

45. Feng Y, Guan XM, Li J, Metzger JM, Zhu Y, Juhl K, Zhang BB, Thornberry NA, Reitman ML, Zhou YP. (2011) Bombesin receptor subtype-3 (BRS-3) regulates glucose-stimulated insulin secretion in pancreatic islets across multiple species. Endocrinology, 152 (11): 4106-15. [PMID:21878513]

46. Fleischmann A, Läderach U, Friess H, Buechler MW, Reubi JC. (2000) Bombesin receptors in distinct tissue compartments of human pancreatic diseases. Lab Invest, 80 (12): 1807-17. [PMID:11140694]

47. Fleming MS, Ramos D, Han SB, Zhao J, Son YJ, Luo W. (2012) The majority of dorsal spinal cord gastrin releasing peptide is synthesized locally whereas neuromedin B is highly expressed in pain- and itch-sensing somatosensory neurons. Mol Pain, 8: 52. [PMID:22776446]

48. Flynn FW. (1997) Bombesin receptor antagonists block the effects of exogenous bombesin but not of nutrients on food intake. Physiol Behav, 62 (4): 791-8. [PMID:9284499]

49. Francl JM, Kaur G, Glass JD. (2010) Roles of light and serotonin in the regulation of gastrin-releasing peptide and arginine vasopressin output in the hamster SCN circadian clock. Eur J Neurosci, 32 (7): 1170-9. [PMID:20731711]

50. Frucht H, Gazdar AF, Park JA, Oie H, Jensen RT. (1992) Characterization of functional receptors for gastrointestinal hormones on human colon cancer cells. Cancer Res, 52 (5): 1114-22. [PMID:1310640]

51. Furutani N, Hondo M, Tsujino N, Sakurai T. (2010) Activation of bombesin receptor subtype-3 influences activity of orexin neurons by both direct and indirect pathways. J Mol Neurosci, 42 (1): 106-11. [PMID:20467915]

52. Gamble KL, Allen GC, Zhou T, McMahon DG. (2007) Gastrin-releasing peptide mediates light-like resetting of the suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation. J Neurosci, 27 (44): 12078-87. [PMID:17978049]

53. Ganter MT, Pittet JF. (2006) Bombesin-like peptides: modulators of inflammation in acute lung injury?. Am J Respir Crit Care Med, 173 (1): 1-2. [PMID:16368789]

54. Gbahou F, Holst B, Schwartz TW. (2010) Molecular basis for agonism in the BB3 receptor: an epitope located on the interface of transmembrane-III, -VI, and -VII. J Pharmacol Exp Ther, 333 (1): 51-9. [PMID:20065020]

55. Ghatei MA, Jung RT, Stevenson JC, Hillyard CJ, Adrian TE, Lee YC, Christofides ND, Sarson DL, Mashiter K, MacIntyre I et al.. (1982) Bombesin: action on gut hormones and calcium in man. J Clin Endocrinol Metab, 54 (5): 980-5. [PMID:7061703]

56. Gonzalez N, Hocart SJ, Portal-Nuñez S, Mantey SA, Nakagawa T, Zudaire E, Coy DH, Jensen RT. (2008) Molecular basis for agonist selectivity and activation of the orphan bombesin receptor subtype 3 receptor. J Pharmacol Exp Ther, 324 (2): 463-74. [PMID:18006692]

57. Gonzalez N, Moody TW, Igarashi H, Ito T, Jensen RT. (2008) Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states. Curr Opin Endocrinol Diabetes Obes, 15 (1): 58-64. [PMID:18185064]

58. González N, Mantey SA, Pradhan TK, Sancho V, Moody TW, Coy DH, Jensen RT. (2009) Characterization of putative GRP- and NMB-receptor antagonist's interaction with human receptors. Peptides, 30 (8): 1473-86. [PMID:19463875]

59. Gorbulev V, Akhundova A, Büchner H, Fahrenholz F. (1992) Molecular cloning of a new bombesin receptor subtype expressed in uterus during pregnancy. Eur J Biochem, 208 (2): 405-10. [PMID:1325907]

60. Gorbulev V, Akhundova A, Grzeschik KH, Fahrenholz F. (1994) Organization and chromosomal localization of the gene for the human bombesin receptor subtype expressed in pregnant uterus. FEBS Lett, 340 (3): 260-4. [PMID:8131855]

61. Gregersen S, Ahrén B. (1996) Studies on the mechanisms by which gastrin releasing peptide potentiates glucose-induced insulin secretion from mouse islets. Pancreas, 12 (1): 48-57. [PMID:8927619]

62. Gregory CA, Schwartz JS. (1991) The cDNA of the human neuromedin B gene (NMB) mapped to 15q11-qter recognizes an XbaI RFLP. Nucleic Acids Res, 19 (5): 1167. [PMID:1673565]

63. Grider JR. (2004) Gastrin-releasing peptide is a modulatory neurotransmitter of the descending phase of the peristaltic reflex. Am J Physiol Gastrointest Liver Physiol, 287 (6): G1109-15. [PMID:15297260]

64. Guan XM, Chen H, Dobbelaar PH, Dong Y, Fong TM, Gagen K, Gorski J, He S, Howard AD, Jian T et al.. (2010) Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity. Cell Metab, 11 (2): 101-12. [PMID:20096642]

65. Guan XM, Metzger JM, Yang L, Raustad KA, Wang SP, Spann SK, Kosinski JA, Yu H, Shearman LP, Faidley TD et al.. (2011) Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist. J Pharmacol Exp Ther, 336 (2): 356-64. [PMID:21036912]

66. Guo C, Guzzo PR, Hadden M, Sargent BJ, Yet L, Kan Y, Palyha O, Kelly TM, Guan X, Rosko K et al.. (2010) Synthesis of 7-benzyl-5-(piperidin-1-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-ylamine and its analogs as bombesin receptor subtype-3 agonists. Bioorg Med Chem Lett, 20 (9): 2785-9. [PMID:20371178]

67. Hadden M, Goodman A, Guo C, Guzzo PR, Henderson AJ, Pattamana K, Ruenz M, Sargent BJ, Swenson B, Yet L et al.. (2010) Synthesis and SAR of heterocyclic carboxylic acid isosteres based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity. Bioorg Med Chem Lett, 20 (9): 2912-5. [PMID:20347296]

68. Hampton LL, Ladenheim EE, Akeson M, Way JM, Weber HC, Sutliff VE, Jensen RT, Wine LJ, Arnheiter H, Battey JF. (1998) Loss of bombesin-induced feeding suppression in gastrin-releasing peptide receptor-deficient mice. Proc Natl Acad Sci USA, 95 (6): 3188-92. [PMID:9501238]

69. Hansen KK, Hauser F, Williamson M, Weber SB, Grimmelikhuijzen CJ. (2011) The Drosophila genes CG14593 and CG30106 code for G-protein-coupled receptors specifically activated by the neuropeptides CCHamide-1 and CCHamide-2. Biochem Biophys Res Commun, 404 (1): 184-9. [PMID:21110953]

70. He S, Dobbelaar PH, Liu J, Jian T, Sebhat IK, Lin LS, Goodman A, Guo C, Guzzo PR, Hadden M et al.. (2010) Discovery of substituted biphenyl imidazoles as potent, bioavailable bombesin receptor subtype-3 agonists. Bioorg Med Chem Lett, 20 (6): 1913-7. [PMID:20167483]

71. Heidary G, Hampton LL, Schanen NC, Rivkin MJ, Darras BT, Battey J, Francke U. (1998) Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome. Am J Med Genet, 78 (2): 173-5. [PMID:9674911]

72. Heimbrook DC, Saari WS, Balishin NL, Fisher TW, Friedman A, Kiefer DM, Rotberg NS, Wallen JW, Oliff A. (1991) Gastrin releasing peptide antagonists with improved potency and stability. J Med Chem, 34 (7): 2102-7. [PMID:2066982]

73. Hermansen K, Ahrén B. (1990) Gastrin releasing peptide stimulates the secretion of insulin, but not that of glucagon or somatostatin, from the isolated perfused dog pancreas. Acta Physiol Scand, 138 (2): 175-9. [PMID:1969219]

74. Hewes RS, Taghert PH. (2001) Neuropeptides and neuropeptide receptors in the Drosophila melanogaster genome. Genome Res, 11 (6): 1126-42. [PMID:11381038]

75. Hildebrand P, Lehmann FS, Ketterer S, Christ AD, Stingelin T, Beltinger J, Gibbons AH, Coy DH, Calam J, Larsen F et al.. (2001) Regulation of gastric function by endogenous gastrin releasing peptide in humans: studies with a specific gastrin releasing peptide receptor antagonist. Gut, 49 (1): 23-8. [PMID:11413106]

76. Hirose T, Okuda K, Yamaoka T, Ishida K, Kusumoto S, Sugiyama T, Shirai T, Ohnshi T, Ohmori T, Adachi M. (2011) Are levels of pro-gastrin-releasing peptide or neuron-specific enolase at relapse prognostic factors after relapse in patients with small-cell lung cancer?. Lung Cancer, 71 (2): 224-8. [PMID:20537424]

77. Hodges LM, Weissman MM, Haghighi F, Costa R, Bravo O, Evgrafov O, Knowles JA, Fyer AJ, Hamilton SP. (2009) Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. Am J Med Genet B Neuropsychiatr Genet, 150B (1): 65-73. [PMID:18452185]

78. Hoggard N, Bashir S, Cruickshank M, Miller JD, Speakman JR. (2007) Expression of neuromedin B in adipose tissue and its regulation by changes in energy balance. J Mol Endocrinol, 39 (3): 199-210. [PMID:17766645]

79. Hou X, Wei L, Harada A, Tatamoto K. (2006) Activation of bombesin receptor subtype-3 stimulates adhesion of lung cancer cells. Lung Cancer, 54 (2): 143-8. [PMID:16979789]

80. Huang SC, Yu DH, Wank SA, Gardner JD, Jensen RT. (1990) Characterization of the bombesin receptor on mouse pancreatic acini by chemical cross-linking. Peptides, 11 (6): 1143-50. [PMID:1708135]

81. Ida T, Takahashi T, Tominaga H, Sato T, Sano H, Kume K, Ozaki M, Hiraguchi T, Shiotani H, Terajima S et al.. (2012) Isolation of the bioactive peptides CCHamide-1 and CCHamide-2 from Drosophila and their putative role in appetite regulation as ligands for G protein-coupled receptors. Front Endocrinol (Lausanne), 3: 177. [PMID:23293632]

82. Ishikawa-Brush Y, Powell JF, Bolton P, Miller AP, Francis F, Willard HF, Lehrach H, Monaco AP. (1997) Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene. Hum Mol Genet, 6 (8): 1241-50. [PMID:9259269]

83. Jeffry J, Kim S, Chen ZF. (2011) Itch signaling in the nervous system. Physiology (Bethesda), 26 (4): 286-92. [PMID:21841076]

84. Jennings CA, Harrison DC, Maycox PR, Crook B, Smart D, Hervieu GJ. (2003) The distribution of the orphan bombesin receptor subtype-3 in the rat CNS. Neuroscience, 120 (2): 309-24. [PMID:12890504]

85. Jensen JA, Carroll RE, Benya RV. (2001) The case for gastrin-releasing peptide acting as a morphogen when it and its receptor are aberrantly expressed in cancer. Peptides, 22 (4): 689-99. [PMID:11311741]

86. Jensen RT. (2004) Gastrin-releasing peptide. In Encyclopedia of Gastroenterology. Edited by Johnson LR (Academic Press-Elsevier Publishing Co.) 179-185. [ISBN:0123868610]

87. Jensen RT, Battey JF, Spindel ER, Benya RV. (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev, 60 (1): 1-42. [PMID:18055507]

88. Jensen RT, Coy DH. (1991) Progress in the development of potent bombesin receptor antagonists. Trends Pharmacol Sci, 12: 13-19. [PMID:1706545]

89. Jensen RT, Moody T, Pert C, Rivier JE, Gardner JD. (1978) Interaction of bombesin and litorin with specific membrane receptors on pancreatic acinar cells. Proc Natl Acad Sci USA, 75 (12): 6139-43. [PMID:216015]

90. Jensen RT, Moody TW. (2006) Bombesin-related peptides and neurotensin: effects on cancer growth/proliferation and cellular signaling in cancer. In Handbook of Biologically Active Peptides. Edited by Kastin AJ (Elsevier) 429-434. [ISBN:9780123694423]

91. Jensen RT, Moody TW. (2013) Bombesin Peptides (Cancer). In Handbook of Biologically Active Peptides. 2nd Revised edition. Edited by Kastin AJ (Elsevier) 506-511. [ISBN:9780123850959]

92. Jensen RT, Moody TW. (2013) Bombesin-Related Peptides. In Handbook of Biologically Active Peptides. 2nd Revised edition. Edited by Kastin AJ (Elsevier) 1188-1196. [ISBN:9780123850959]

93. Jones PM, Withers DJ, Ghatei MA, Bloom SR. (1992) Evidence for neuromedin-B synthesis in the rat anterior pituitary gland. Endocrinology, 130 (4): 1829-36. [PMID:1547712]

94. Kamichi S, Wada E, Aoki S, Sekiguchi M, Kimura I, Wada K. (2005) Immunohistochemical localization of gastrin-releasing peptide receptor in the mouse brain. Brain Res, 1032 (1-2): 162-70. [PMID:15680955]

95. Karlsson S, Sundler F, Ahrén B. (1998) Insulin secretion by gastrin-releasing peptide in mice: ganglionic versus direct islet effect. Am J Physiol, 274 (1): E124-9. [PMID:9458757]

96. Katsuno T, Pradhan TK, Ryan RR, Mantey SA, Hou W, Donohue PJ, Akeson MA, Spindel ER, Battey JF, Coy DH et al.. (1999) Pharmacology and cell biology of the bombesin receptor subtype 4 (BB4-R). Biochemistry, 38 (22): 7307-20. [PMID:10353842]

97. Kilgore WR, Mantyh PW, Mantyh CR, McVey DC, Vigna SR. (1993) Bombesin/GRP-preferring and neuromedin B-preferring receptors in the rat urogenital system. Neuropeptides, 24: 43-52. [PMID:8381528]

98. Kim JB, Johansson A, Holmgren S, Conlon JM. (2001) Gastrin-releasing peptides from Xenopus laevis: purification, characterization, and myotropic activity. Am J Physiol Regul Integr Comp Physiol, 281 (3): R902-8. [PMID:11507007]

99. Koga K, Chen T, Li XY, Descalzi G, Ling J, Gu J, Zhuo M. (2011) Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord. Mol Pain, 7: 47. [PMID:21699733]

100. Krane IM, Naylor SL, Helin-Davis D, Chin WW, Spindel ER. (1988) Molecular cloning of cDNAs encoding the human bombesin-like peptide neuromedin B. Chromosomal localization and comparison to cDNAs encoding its amphibian homolog ranatensin. J Biol Chem, 263 (26): 13317-23. [PMID:2458345]

101. Kusui T, Benya RV, Battey JF, Jensen RT. (1994) Glycosylation of bombesin receptors: characterization, effect on binding, and G-protein coupling. Biochemistry, 33 (44): 12968-80. [PMID:7947701]

102. Kusui T, Hellmich MR, Wang LH, Evans RL, Benya RV, Battey JF, Jensen RT. (1995) Characterization of gastrin-releasing peptide receptor expressed in Sf9 insect cells by baculovirus. Biochemistry, 34: 8061-8075. [PMID:7794919]

103. Ladenheim EE. (2013) Bombesin. In Handbook of Biologically Active Peptides. Edited by Kastin AJ (Elsevier) 1064-1070. [ISBN:9780123694423]

104. Ladenheim EE, Hamilton NL, Behles RR, Bi S, Hampton LL, Battey JF, Moran TH. (2008) Factors contributing to obesity in bombesin receptor subtype-3-deficient mice. Endocrinology, 149 (3): 971-8. [PMID:18039774]

105. Ladenheim EE, Hampton LL, Whitney AC, White WO, Battey JF, Moran TH. (2002) Disruptions in feeding and body weight control in gastrin-releasing peptide receptor deficient mice. Journal of Endocrinology, 174: 273-281. [PMID:12176666]

106. Ladenheim EE, Jensen RT, Mantey SA, Moran TH. (1992) Distinct distributions of two bombesin receptor subtypes in the rat central nervous system. Brain Res, 593 (2): 168-78. [PMID:1333344]

107. Ladenheim EE, Knipp S. (2007) Capsaicin treatment differentially affects feeding suppression by bombesin-like peptides. Physiol Behav, 91 (1): 36-41. [PMID:17343884]

108. Ladenheim EE, Taylor JE, Coy DH, Carrigan TS, Wohn A, Moran TH. (1997) Caudal hindbrain neuromedin B-preferring receptors participate in the control of food intake. Am J Physiol, 272 (1 Pt 2): R433-7. [PMID:9039040]

109. Ladenheim EE, Taylor JE, Coy DH, Moran TH. (1994) Blockade of feeding inhibition by neuromedin B using a selective receptor antagonist. Eur J Pharmacol, 271 (1): R7-9. [PMID:7698191]

110. Ladenheim EE, Wirth KE, Moran TH. (1996) Receptor subtype mediation of feeding suppression by bombesin-like peptides. Pharmacol Biochem Behav, 54: 705-711. [PMID:8853193]

111. Lango MN, Dyer KF, Lui VW, Gooding WE, Gubish C, Siegfried JM, Grandis JR. (2002) Gastrin-releasing peptide receptor-mediated autocrine growth in squamous cell carcinoma of the head and neck. J Natl Cancer Inst, 94 (5): 375-83. [PMID:11880476]

112. Lebacq-Verheyden AM, Bertness V, Kirsch I, Hollis GF, McBride OW, Battey J. (1987) Human gastrin-releasing peptide gene maps to chromosome band 18q21. Somat Cell Mol Genet, 13 (1): 81-6. [PMID:3027901]

113. Lehmann FS, Beglinger C. (2006) Gastrin-releasing peptide. In Handbook of Biologically Active Peptides. Edited by Kastin AJ (Academic Press-Elsevier) 1044-1055. [ISBN:0123694426]

114. Lin JT, Coy DH, Mantey SA, Jensen RT. (1995) Comparison of the peptide structural requirements for high affinity interaction with bombesin receptors. Eur J Pharmacol, 294 (1): 55-69. [PMID:8788416]

115. Liu HJ, Tan YR, Li ML, Liu C, Xiang Y, Qin XQ. (2011) Cloning of a novel protein interacting with BRS-3 and its effects in wound repair of bronchial epithelial cells. PLoS ONE, 6 (8): e23072. [PMID:21857995]

116. Liu J, He S, Jian T, Dobbelaar PH, Sebhat IK, Lin LS, Goodman A, Guo C, Guzzo PR, Hadden M et al.. (2010) Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity. Bioorg Med Chem Lett, 20 (7): 2074-7. [PMID:20219372]

117. Liu J, Lao ZJ, Zhang J, Schaeffer MT, Jiang MM, Guan XM, Van der Ploeg LH, Fong TM. (2002) Molecular basis of the pharmacological difference between rat and human bombesin receptor subtype-3 (BRS-3). Biochemistry, 41 (28): 8954-60. [PMID:12102638]

118. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X. (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell, 139 (7): 1353-65. [PMID:20004959]

119. Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH et al.. (2011) Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell, 147 (2): 447-58. [PMID:22000021]

120. Lo MM, Chobanian HR, Palyha O, Kan Y, Kelly TM, Guan XM, Reitman ML, Dragovic J, Lyons KA, Nargund RP et al.. (2011) Pyridinesulfonylureas and pyridinesulfonamides as selective bombesin receptor subtype-3 (BRS-3) agonists. Bioorg Med Chem Lett, 21 (7): 2040-3. [PMID:21354793]

121. Maekawa F, Quah HM, Tanaka K, Ohki-Hamazaki H. (2004) Leptin resistance and enhancement of feeding facilitation by melanin-concentrating hormone in mice lacking bombesin receptor subtype-3. Diabetes, 53 (3): 570-6. [PMID:14988239]

122. Majumdar ID, Weber HC. (2011) Biology of mammalian bombesin-like peptides and their receptors. Curr Opin Endocrinol Diabetes Obes, 18 (1): 68-74. [PMID:21042212]

123. Majumdar ID, Weber HC. (2012) Appetite-modifying effects of bombesin receptor subtype-3 agonists. Handb Exp Pharmacol, (209): 405-32. [PMID:22249826]

124. Majumdar ID, Weber HC. (2012) Biology and pharmacology of bombesin receptor subtype-3. Curr Opin Endocrinol Diabetes Obes, 19 (1): 3-7. [PMID:22157398]

125. Mantey S, Frucht H, Coy DH, Jensen RT. (1993) Characterization of bombesin receptors using a novel, potent, radiolabeled antagonist that distinguishes bombesin receptor subtypes. Mol Pharmacol, 43 (5): 762-74. [PMID:7684815]

126. Mantey SA, Coy DH, Entsuah LK, Jensen RT. (2004) Development of bombesin analogs with conformationally restricted amino acid substitutions with enhanced selectivity for the orphan receptor human bombesin receptor subtype 3. J Pharmacol Exp Ther, 310 (3): 1161-70. [PMID:15102928]

127. Mantey SA, Coy DH, Pradhan TK, Igarashi H, Rizo IM, Shen L, Hou W, Hocart SJ, Jensen RT. (2001) Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3. J Biol Chem, 276 (12): 9219-29. [PMID:11112777]

128. Mantey SA, Gonzalez N, Schumann M, Pradhan TK, Shen L, Coy DH, Jensen RT. (2006) Identification of bombesin receptor subtype-specific ligands: effect of N-methyl scanning, truncation, substitution, and evaluation of putative reported selective ligands. J Pharmacol Exp Ther, 319 (2): 980-9. [PMID:16943256]

129. Mantey SA, Weber HC, Sainz E, Akeson M, Ryan RR, Pradhan TK, Searles RP, Spindel ER, Battey JF, Coy DH et al.. (1997) Discovery of a high affinity radioligand for the human orphan receptor, bombesin receptor subtype 3, which demonstrates that it has a unique pharmacology compared with other mammalian bombesin receptors. J Biol Chem, 272 (41): 26062-71. [PMID:9325344]

130. Marui T, Hashimoto O, Nanba E, Kato C, Tochigi M, Umekage T, Kato N, Sasaki T. (2004) Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism. Brain Dev, 26 (1): 5-7. [PMID:14729406]

131. Maslen GL, Boyd Y. (1993) Comparative mapping of the Grpr locus on the X chromosomes of man and mouse. Genomics, 17 (1): 106-9. [PMID:8406441]

132. Matsumoto K, Yamada K, Wada E, Hasegawa T, Usui Y, Wada K. (2003) Bombesin receptor subtype-3 modulates plasma insulin concentration. Peptides, 24 (1): 83-90. [PMID:12576088]

133. Matusiak D, Glover S, Nathaniel R, Matkowskyj K, Yang J, Benya RV. (2005) Neuromedin B and its receptor are mitogens in both normal and malignant epithelial cells lining the colon. Am J Physiol Gastrointest Liver Physiol, 288 (4): G718-28. [PMID:15528253]

134. McDonald TJ, Ghatei MA, Bloom SR, Adrian TE, Mochizuki T, Yanaihara C, Yanaihara N. (1983) Dose-response comparisons of canine plasma gastroenteropancreatic hormone responses to bombesin and the porcine gastrin-releasing peptide (GRP). Regul Pept, 5: 125-137. [PMID:6338565]

135. McDonald TJ, Jörnvall H, Nilsson G, Vagne M, Ghatei M, Bloom SR, Mutt V. (1979) Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun, 90 (1): 227-33. [PMID:496973]

136. Medina S, Del Rio M, Ferrández MD, Hernanz A, De la Fuente M. (1998) Changes with age in the modulation of natural killer activity of murine leukocytes by gastrin-releasing peptide, neuropeptide Y and sulfated cholecystokinin octapeptide. Neuropeptides, 32 (6): 549-55. [PMID:9920453]

137. Medina S, Del Río M, Manuel Victor V, Hernánz A, De la Fuente M. (1998) Changes with ageing in the modulation of murine lymphocyte chemotaxis by CCK-8S, GRP and NPY. Mech Ageing Dev, 102 (2-3): 249-61. [PMID:9720656]

138. Merali Z, Bédard T, Andrews N, Davis B, McKnight AT, Gonzalez MI, Pritchard M, Kent P, Anisman H. (2006) Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity. J Neurosci, 26 (41): 10387-96. [PMID:17035523]

139. Merali Z, Kent P, Anisman H. (2002) Role of bombesin-related peptides in the mediation or integration of the stress response. Cell Mol Life Sci, 59 (2): 272-87. [PMID:11915944]

140. Merali Z, McIntosh J, Anisman H. (1999) Role of bombesin-related peptides in the control of food intake. Neuropeptides, 33: 376-386. [PMID:10657515]

141. Metzger JM, Gagen K, Raustad KA, Yang L, White A, Wang SP, Craw S, Liu P, Lanza T, Lin LS et al.. (2010) Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments. Am J Physiol Endocrinol Metab, 299 (5): E816-24. [PMID:20807840]

142. Mihara S, Hara M, Nakamura M, Sakurawi K, Tokura K, Fujimoto M, Fukai T, Nomura T. (1995) Non-peptide bombesin receptor antagonists, kuwanon G and H, isolated from mulberry. Biochem Biophys Res Commun, 213 (2): 594-9. [PMID:7646517]

143. Milusheva EA, Kortezova NI, Mizhorkova ZN, Papasova M, Coy DH, Bálint A, Vizi ES, Varga G. (1998) Role of different bombesin receptor subtypes mediating contractile activity in cat upper gastrointestinal tract. Peptides, 19 (3): 549-56. [PMID:9533644]

144. Minamino N, Kangawa K, Matsuo H. (1983) Neuromedin B: a novel bombesin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun, 114: 541-548. [PMID:6882442]

145. Minamino N, Kangawa K, Matsuo H. (1984) Neuromedin C: a bombesin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun, 119 (1): 14-20. [PMID:6546686]

146. Mishra SK, Holzman S, Hoon MA. (2012) A nociceptive signaling role for neuromedin B. J Neurosci, 32 (25): 8686-95. [PMID:22723708]

147. Mishra SK, Hoon MA. (2013) The cells and circuitry for itch responses in mice. Science, 340 (6135): 968-71. [PMID:23704570]

148. Moody TW, Berna MJ, Mantey S, Sancho V, Ridnour L, Wink DA, Chan D, Giaccone G, Jensen RT. (2010) Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells. Eur J Pharmacol, 637 (1-3): 38-45. [PMID:20388507]

149. Moody TW, Chan D, Fahrenkrug J, Jensen RT. (2003) Neuropeptides as autocrine growth factors in cancer cells. Curr Pharm Des, 9 (6): 495-509. [PMID:12570813]

150. Moody TW, Fagarasan M, Zia F. (1995) Neuromedin B stimulates arachidonic acid release, c-fos gene expression, and the growth of C6 glioma cells. Peptides, 16 (6): 1133-40. [PMID:8532598]

151. Moody TW, Mantey SA, Pradhan TK, Schumann M, Nakagawa T, Martinez A, Fuselier J, Coy DH, Jensen RT. (2004) Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells. J Biol Chem, 279 (22): 23580-9. [PMID:15016826]

152. Moody TW, Merali Z. (2004) Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides, 25: 511-520. [PMID:15134870]

153. Moody TW, Sancho V, di Florio A, Nuche-Berenguer B, Mantey S, Jensen RT. (2011) Bombesin receptor subtype-3 agonists stimulate the growth of lung cancer cells and increase EGF receptor tyrosine phosphorylation. Peptides, 32 (8): 1677-84. [PMID:21712056]

154. Moody TW, Sun LC, Mantey SA, Pradhan T, Mackey LV, Gonzales N, Fuselier JA, Coy DH, Jensen RT. (2006) In vitro and in vivo antitumor effects of cytotoxic camptothecin-bombesin conjugates are mediated by specific interaction with cellular bombesin receptors. J Pharmacol Exp Ther, 318 (3): 1265-72. [PMID:16766720]

155. Moreno P, Mantey SA, Nuche-Berenguer B, Reitman ML, Gonzalez N, , Coy DH, Jensen RT. (2013) Comparative Pharmacology of Bombesin Receptor Subtype-3, Nonpeptide Agonist MK-5046, a Universal Peptide Agonist, and Peptide Antagonist Bantag-1 for Human Bombesin Receptors. Pharmacol Exp Therap, 347 (1): 100-116. [PMID:23892571]

156. Myklebust AT, Godal A, Pharo A, Juell S, Fodstad O. (1993) Eradication of small cell lung cancer cells from human bone marrow with immunotoxins. Cancer Res, 53 (16): 3784-8. [PMID:8393381]

157. Nagalla SR, Barry BJ, Creswick KC, Eden P, Taylor JT, Spindel ER. (1995) Cloning of a receptor for amphibian [Phe13]bombesin distinct from the receptor for gastrin-releasing peptide: identification of a fourth bombesin receptor subtype (BB4). Proc Natl Acad Sci USA, 92 (13): 6205-9. [PMID:7597102]

158. Nagalla SR, Gibson BW, Tang D, Reeve Jr JR, Spindel ER. (1992) Gastrin-releasing peptide (GRP) is not mammalian bombesin. Identification and molecular cloning of a true amphibian GRP distinct from amphibian bombesin in Bombina orientalis. J Biol Chem, 267 (10): 6916-22. [PMID:1551901]

159. Nakamichi Y, Wada E, Aoki K, Ohara-Imaizumi M, Kikuta T, Nishiwaki C, Matsushima S, Watanabe T, Wada K, Nagamatsu S. (2004) Functions of pancreatic beta cells and adipocytes in bombesin receptor subtype-3-deficient mice. Biochem Biophys Res Commun, 318 (3): 698-703. [PMID:15144894]

160. Naylor SL, Sakaguchi AY, Spindel E, Chin WW. (1987) Human gastrin-releasing peptide gene is located on chromosome 18. Somat Cell Mol Genet, 13 (1): 87-91. [PMID:3027902]

161. Nisman B, Biran H, Ramu N, Heching N, Barak V, Peretz T. (2009) The diagnostic and prognostic value of ProGRP in lung cancer. Anticancer Res, 29 (11): 4827-32. [PMID:20032442]

162. Ohki-Hamazaki H. (2000) Neuromedin B. Prog Neurobiol, 62 (3): 297-312. [PMID:10840151]

163. Ohki-Hamazaki H, Sakai Y, Kamata K, Ogura H, Okuyama S, Watase K, Yamada K, Wada K. (1999) Functional properties of two bombesin-like peptide receptors revealed by the analysis of mice lacking neuromedin B receptor. J Neurosci, 19 (3): 948-54. [PMID:9920658]

164. Ohki-Hamazaki H, Wada E, Matsui K, Wada K. (1997) Cloning and expression of the neuromedin B receptor and the third subtype of bombesin receptor genes in the mouse. Brain Res, 762 (1-2): 165-72. [PMID:9262170]

165. Ohki-Hamazaki H, Watase K, Yamamoto K, Ogura H, Yamano M, Yamada K, Maeno H, Imaki J, Kikuyama S, Wada E et al.. (1997) Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity. Nature, 390 (6656): 165-9. [PMID:9367152]

166. Okarvi SM. (2008) Peptide-based radiopharmaceuticals and cytotoxic conjugates: potential tools against cancer. Cancer Treat Rev, 34 (1): 13-26. [PMID:17870245]

167. Oliveira KJ, Cabanelas A, Veiga MA, Paula GS, Ortiga-Carvalho TM, Wada E, Wada K, Pazos-Moura CC. (2008) Impaired serum thyrotropin response to hypothyroidism in mice with disruption of neuromedin B receptor. Regul Pept, 146 (1-3): 213-7. [PMID:17931717]

168. Oliveira KJ, Ortiga-Carvalho TM, Cabanelas A, Veiga MA, Aoki K, Ohki-Hamazaki H, Wada K, Wada E, Pazos-Moura CC. (2006) Disruption of neuromedin B receptor gene results in dysregulation of the pituitary-thyroid axis. J Mol Endocrinol, 36 (1): 73-80. [PMID:16461928]

169. Oliveira PG, Brenol CV, Edelweiss MI, Brenol JC, Petronilho F, Roesler R, Dal-Pizzol F, Schwartsmann G, Xavier RM. (2008) Effects of an antagonist of the bombesin/gastrin-releasing peptide receptor on complete Freund's adjuvant-induced arthritis in rats. Peptides, 29 (10): 1726-31. [PMID:18590783]

170. Ono A, Naito T, Ito I, Watanabe R, Shukuya T, Kenmotsu H, Tsuya A, Nakamura Y, Murakami H, Kaira K et al.. (2012) Correlations between serial pro-gastrin-releasing peptide and neuron-specific enolase levels, and the radiological response to treatment and survival of patients with small-cell lung cancer. Lung Cancer, 76 (3): 439-44. [PMID:22300752]

171. Oremek GM, Sapoutzis N. (2003) Pro-gastrin-releasing peptide (Pro-GRP), a tumor marker for small cell lung cancer. Anticancer Res, 23 (2A): 895-8. [PMID:12820319]

172. Ortiga-Carvalho TM, Curty FH, Nascimento-Saba CC, Moura EG, Polak J, Pazos-Moura CC. (1997) Pituitary neuromedin B content in experimental fasting and diabetes mellitus and correlation with thyrotropin secretion. Metab Clin Exp, 46 (2): 149-53. [PMID:9030820]

173. Ortiga-Carvalho TM, Oliveira Kde J, Morales MM, Martins VP, Pazos-Moura CC. (2003) Thyrotropin secretagogues reduce rat pituitary neuromedin B, a local thyrotropin release inhibitor. Exp Biol Med (Maywood), 228 (9): 1083-8. [PMID:14530520]

174. Parkman HP, Vozzelli MA, Pagano AP, Cowan A. (1994) Pharmacological analysis of receptors for bombesin-related peptides on guinea pig gallbladder smooth muscle. Regul Pept, 52 (3): 173-80. [PMID:7800849]

175. Patel O, Shulkes A, Baldwin GS. (2006) Gastrin-releasing peptide and cancer. Biochim Biophys Acta, 1766 (1): 23-41. [PMID:16490321]

176. Paula GS, Souza LL, Cabanelas A, Bloise FF, Mello-Coelho V, Wada E, Ortiga-Carvalho TM, Oliveira KJ, Pazos-Moura CC. (2010) Female mice target deleted for the neuromedin B receptor have partial resistance to diet-induced obesity. J Physiol (Lond.), 588 (Pt 9): 1635-45. [PMID:20211980]

177. Pazos-Moura CC, Moura EG, Rettori V, Polak J, McCann SM. (1996) Role of neuromedin B in the in vitro thyrotropin release in response to thyrotropin-releasing hormone from anterior pituitaries of eu-, hypo-, and hyperthyroid rats. Proc Soc Exp Biol Med, 211 (4): 353-8. [PMID:8618941]

178. Pazos-Moura CC, Ortiga TM, Curty FH, Moreira RM, Lisboa PC. (1993) Paradoxical effect of neuromedin B and thyroxin on thyrotropin secretion from isolated hyperthyroid pituitaries. Braz J Med Biol Res, 26 (12): 1349-54. [PMID:8136736]

179. Pazos-Moura CC, Ortiga-Carvalho TM, Gaspar de Moura E. (2003) The autocrine/paracrine regulation of thyrotropin secretion. Thyroid, 13: 167-175. [PMID:12699591]

180. Pereira DV, Steckert AV, Mina F, Petronilho F, Roesler R, Schwartsmann G, Ritter C, Dal-Pizzol F. (2009) Effects of an antagonist of the gastrin-releasing peptide receptor in an animal model of uveitis. Invest Ophthalmol Vis Sci, 50 (11): 5300-3. [PMID:19516017]

181. Persson K, Pacini G, Sundler F, Ahrén B. (2002) Islet function phenotype in gastrin-releasing peptide receptor gene-deficient mice. Endocrinology, 143 (10): 3717-26. [PMID:12239081]

182. Petronilho F, Danielski LG, Roesler R, Schwartsmann G, Dal-Pizzol F. (2013) Gastrin-releasing peptide as a molecular target for inflammatory diseases: an update. Inflamm Allergy Drug Targets, 12 (3): 172-7. [PMID:23621446]

183. Petronilho F, Vuolo F, Galant LS, Constantino L, Tomasi CD, Giombelli VR, de Souza CT, da Silva S, Barbeiro DF, Soriano FG et al.. (2012) Gastrin-releasing peptide receptor antagonism induces protection from lethal sepsis: involvement of toll-like receptor 4 signaling. Mol Med, 18: 1209-19. [PMID:22735756]

184. Pigeyre M, Bokor S, Romon M, Gottrand F, Gilbert CC, Valtueña J, Gómez-Martínez S, Moreno LA, Amouyel P, Dallongeville J et al.. (2010) Influence of maternal educational level on the association between the rs3809508 neuromedin B gene polymorphism and the risk of obesity in the HELENA study. Int J Obes (Lond.), 34 (3): 478-86. [PMID:20010906]

185. Plonowski A, Nagy A, Schally AV, Sun B, Groot K, Halmos G. (2000) In vivo inhibition of PC-3 human androgen-independent prostate cancer by a targeted cytotoxic bombesin analogue, AN-215. Int J Cancer, 88 (4): 652-7. [PMID:11058885]

186. Porcher C, Juhem A, Peinnequin A, Bonaz B. (2005) Bombesin receptor subtype-3 is expressed by the enteric nervous system and by interstitial cells of Cajal in the rat gastrointestinal tract. Cell Tissue Res, 320 (1): 21-31. [PMID:15726424]

187. Pradhan TK, Katsuno T, Taylor JE, Kim SH, Ryan RR, Mantey SA, Donohue PJ, Weber HC, Sainz E, Battey JF et al.. (1998) Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes. Eur J Pharmacol, 343 (2-3): 275-87. [PMID:9570477]

188. Price J, Penman E, Wass JA, Rees LH. (1984) Bombesin-like immunoreactivity in human gastrointestinal tract. Regul Pept, 9 (1-2): 1-10. [PMID:6505289]

189. Pujatti PB, Santos JS, Couto RM, Melero LT, Suzuki MF, Soares CR, Grallert SR, Mengatti J, De Araújo EB. (2011) Novel series of (177)Lu-labeled bombesin derivatives with amino acidic spacers for selective targeting of human PC-3 prostate tumor cells. Q J Nucl Med Mol Imaging, 55 (3): 310-23. [PMID:21532543]

190. Qin XQ, Qu X. (2013) Extraintestinal roles of bombesin-like peptides and their receptors: lung. Curr Opin Endocrinol Diabetes Obes, 20 (1): 22-6. [PMID:23222852]

191. Qu X, Li M, Liu HJ, Xiang Y, Tan Y, Weber HC, Qin XQ. (2013) Role of bombesin receptor activated protein in the antigen presentation by human bronchial epithelial cells. J Cell Biochem, 114 (1): 238-44. [PMID:22930588]

192. Ramos-Álvarez I, Martín-Duce A, Moreno-Villegas Z, Sanz R, Aparicio C, Portal-Núñez S, Mantey SA, Jensen RT, González N. (2013) Bombesin receptor subtype-3 (BRS-3), a novel candidate as therapeutic molecular target in obesity and diabetes. Mol Cell Endocrinol, 367 (1-2): 109-15. [PMID:23291341]

193. Reeve Jr JR, Cuttitta F, Vigna SR, Shively JE, Walsh JH. (1988) Processing of mammalian preprogastrin-releasing peptide. Ann N Y Acad Sci, 547: 21-9. [PMID:3071218]

194. Reitman ML, Dishy V, Moreau A, Denney WS, Liu C, Kraft WK, Mejia AV, Matson MA, Stoch SA, Wagner JA et al.. (2012) Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients. J Clin Pharmacol, 52 (9): 1306-16. [PMID:22162541]

195. Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer JC, Gugger M. (2002) Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-[D-TYR(6), beta-ALA(11), PHE(13), NLE(14)] bombesin(6-14). Clin Cancer Res, 8 (4): 1139-46. [PMID:11948125]

196. Rick FG, Abi-Chaker A, Szalontay L, Perez R, Jaszberenyi M, Jayakumar AR, Shamaladevi N, Szepeshazi K, Vidaurre I, Halmos G et al.. (2013) Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist. Proc Natl Acad Sci USA, 110 (7): 2617-22. [PMID:23359692]

197. Rick FG, Buchholz S, Schally AV, Szalontay L, Krishan A, Datz C, Stadlmayr A, Aigner E, Perez R, Seitz S et al.. (2012) Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers. Cell Cycle, 11 (13): 2518-25. [PMID:22751419]

198. Roesler R, Henriques JA, Schwartsmann G. (2004) Neuropeptides and anxiety disorders: bombesin receptors as novel therapeutic targets. Trends Pharmacol Sci, 25 (5): 241-2; author reply 242-3. [PMID:15120487]

199. Roesler R, Henriques JA, Schwartsmann G. (2006) Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets, 5 (2): 197-204. [PMID:16611092]

200. Roesler R, Kapczinski F, Quevedo J, Dal Pizzol F, Schwartsmann G. (2007) The gastrin-releasing peptide receptor as a therapeutic target in central nervous system disorders. Recent Pat CNS Drug Discov, 2 (2): 125-9. [PMID:18221223]

201. Roesler R, Kent P, Schroder N, Schwartsmann G, Merali Z. (2012) Bombesin receptor regulation of emotional memory. Rev Neurosci, 23 (5-6): 571-86. [PMID:23096238]

202. Roesler R, Schwartsmann G. (2012) Gastrin-releasing peptide receptors in the central nervous system: role in brain function and as a drug target. Front Endocrinol (Lausanne), 3: 159. [PMID:23251133]

203. Roesler R, Valvassori SS, Castro AA, Luft T, Schwartsmann G, Quevedo J. (2009) Phosphoinositide 3-kinase is required for bombesin-induced enhancement of fear memory consolidation in the hippocampus. Peptides, 30 (6): 1192-6. [PMID:19463755]

204. Rouissi N, Rhaleb NE, Nantel F, Dion S, Drapeau G, Regoli D. (1991) Characterization of bombesin receptors in peripheral contractile organs. Br J Pharmacol, 103 (1): 1141-7. [PMID:1652341]

205. Ruff M, Schiffmann E, Terranova V, Pert CB. (1985) Neuropeptides are chemoattractants for human tumor cells and monocytes: a possible mechanism for metastasis. Clin Immunol Immunopathol, 37 (3): 387-96. [PMID:2414046]

206. Ryan RR, Katsuno T, Mantey SA, Pradhan TK, Weber HC, Coy DH, Battey JF, Jensen RT. (1999) Comparative pharmacology of the nonpeptide neuromedin B receptor antagonist PD 168368. J Pharmacol Exp Ther, 290 (3): 1202-11. [PMID:10454496]

207. Ryan RR, Weber HC, Hou W, Sainz E, Mantey SA, Battey JF, Coy DH, Jensen RT. (1998) Ability of various bombesin receptor agonists and antagonists to alter intracellular signaling of the human orphan receptor BRS-3. J Biol Chem, 273 (22): 13613-24. [PMID:9593699]

208. Ryan RR, Weber HC, Mantey SA, Hou W, Hilburger ME, Pradhan TK, Coy DH, Jensen RT. (1998) Pharmacology and intracellular signaling mechanisms of the native human orphan receptor BRS-3 in lung cancer cells. J Pharmacol Exp Ther, 287 (1): 366-80. [PMID:9765358]

209. Sakamoto H. (2011) Gastrin-releasing peptide system in the spinal cord mediates masculine sexual function. Anat Sci Int, 86 (1): 19-29. [PMID:21104362]

210. Sakamoto H, Kawata M. (2009) Gastrin-releasing peptide system in the spinal cord controls male sexual behaviour. J Neuroendocrinol, 21 (4): 432-5. [PMID:19187464]

211. Sakamoto H, Matsuda K, Zuloaga DG, Hongu H, Wada E, Wada K, Jordan CL, Breedlove SM, Kawata M. (2008) Sexually dimorphic gastrin releasing peptide system in the spinal cord controls male reproductive functions. Nat Neurosci, 11 (6): 634-6. [PMID:18488022]

212. Sakamoto H, Matsuda K, Zuloaga DG, Nishiura N, Takanami K, Jordan CL, Breedlove SM, Kawata M. (2009) Stress affects a gastrin-releasing peptide system in the spinal cord that mediates sexual function: implications for psychogenic erectile dysfunction. PLoS ONE, 4 (1): e4276. [PMID:19169356]

213. Sakamoto H, Takanami K, Zuloaga DG, Matsuda K, Jordan CL, Breedlove SM, Kawata M. (2009) Androgen regulates the sexually dimorphic gastrin-releasing peptide system in the lumbar spinal cord that mediates male sexual function. Endocrinology, 150 (8): 3672-9. [PMID:19359382]

214. Sancho V, Di Florio A, Moody TW, Jensen RT. (2011) Bombesin receptor-mediated imaging and cytotoxicity: review and current status. Curr Drug Deliv, 8 (1): 79-134. [PMID:21034419]

215. Sano H, Feighner SD, Hreniuk DL, Iwaasa H, Sailer AW, Pan J, Reitman ML, Kanatani A, Howard AD, Tan CP. (2004) Characterization of the bombesin-like peptide receptor family in primates. Genomics, 84 (1): 139-46. [PMID:15203211]

216. Sausville EA, Lebacq-Verheyden AM, Spindel ER, Cuttitta F, Gazdar AF, Battey JF. (1986) Expression of the gastrin-releasing peptide gene in human small cell lung cancer. Evidence for alternative processing resulting in three distinct mRNAs. J Biol Chem, 261 (5): 2451-7. [PMID:3003116]

217. Schally AV, Engel JB, Emons G, Block NL, Pinski J. (2011) Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors. Curr Drug Deliv, 8 (1): 11-25. [PMID:21034424]

218. Schally AV, Nagy A. (2004) Chemotherapy targeted to cancers through tumoral hormone receptors. Trends Endocrinol Metab, 15 (7): 300-10. [PMID:15350601]

219. Schroeder RP, van Weerden WM, Bangma C, Krenning EP, de Jong M. (2009) Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues. Methods, 48 (2): 200-4. [PMID:19398012]

220. Schubert ML. (1999) Regulation of gastric acid secretion. Curr Opin Gastroenterol, 15 (6): 457-62. [PMID:17023991]

221. Schulz S, Röcken C, Schulz S. (2006) Immunohistochemical detection of bombesin receptor subtypes GRP-R and BRS-3 in human tumors using novel antipeptide antibodies. Virchows Arch, 449 (4): 421-7. [PMID:16967266]

222. Sebhat IK, Franklin C, Lo MM, Chen D, Jewell JP, Miller R, Pang J, Palyha O, Kan Y, Kelly TM et al.. (2011) Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity. ACS Med Chem Lett, 2 (1): 43-7. [PMID:24900253]

223. Severi C, Jensen RT, Erspamer V, D'Arpino L, Coy DH, Torsoli A, Delle Fave G. (1991) Different receptors mediate the action of bombesin-related peptides on gastric smooth muscle cells. Am J Physiol, 260: G683-G690. [PMID:1852115]

224. Shan L, Emanuel RL, Dewald D, Torday JS, Asokanathan N, Wada K, Wada E, Sunday ME. (2004) Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung. Am J Physiol Lung Cell Mol Physiol, 286 (1): L165-73. [PMID:12959933]

225. Sharif TR, Luo W, Sharif M. (1997) Functional expression of bombesin receptor in most adult and pediatric human glioblastoma cell lines; role in mitogenesis and in stimulating the mitogen-activated protein kinase pathway. Mol Cell Endocrinol, 130 (1-2): 119-30. [PMID:9220028]

226. Siegfried JM, Krishnamachary N, Gaither Davis A, Gubish C, Hunt JD, Shriver SP. (1999) Evidence for autocrine actions of neuromedin B and gastrin-releasing peptide in non-small cell lung cancer. Pulm Pharmacol Ther, 12 (5): 291-302. [PMID:10545285]

227. Smith CJ, Volkert WA, Hoffman TJ. (2003) Gastrin releasing peptide (GRP) receptor targeted radiopharmaceuticals: a concise update. Nucl Med Biol, 30 (8): 861-8. [PMID:14698790]

228. Sotomayor S, Muñoz-Moreno L, Carmena MJ, Schally AV, Sánchez-Chapado M, Prieto JC, Bajo AM. (2010) Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN-215) and a bombesin antagonist (RC-3095). Int J Cancer, 127 (8): 1813-22. [PMID:20099275]

229. Spindel ER. (2013) Bombesin Peptides. In Handbook of Biologically Active Peptides. Edited by Kastin AJ (Elsevier) 325-330. [ISBN:9780123694423]

230. Spindel ER, Chin WW, Price J, Rees LH, Besser GM, Habener JF. (1984) Cloning and characterization of cDNAs encoding human gastrin-releasing peptide. Proc Natl Acad Sci USA, 81 (18): 5699-703. [PMID:6207529]

231. Spindel ER, Giladi E, Brehm P, Goodman RH, Segerson TP. (1990) Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. Mol Endocrinol, 4: 1956-1963. [PMID:1707129]

232. Spálová J, Zamrazilová H, Vcelák J, Vanková M, Lukásová P, Hill M, Hlavatá K, Srámková P, Fried M, Aldhoon B et al.. (2008) Neuromedin beta: P73T polymorphism in overweight and obese subjects. Physiol Res, 57 Suppl 1: S39-48. [PMID:18271693]

233. Stieber P, Dienemann H, Schalhorn A, Schmitt UM, Reinmiedl J, Hofmann K, Yamaguchi K. (1999) Pro-gastrin-releasing peptide (ProGRP)--a useful marker in small cell lung carcinomas. Anticancer Res, 19 (4A): 2673-8. [PMID:10470218]

234. Strug LJ, Suresh R, Fyer AJ, Talati A, Adams PB, Li W, Hodge SE, Gilliam TC, Weissman MM. (2010) Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry, 15 (2): 166-76. [PMID:18663369]

235. Su PY, Ko MC. (2011) The role of central gastrin-releasing peptide and neuromedin B receptors in the modulation of scratching behavior in rats. J Pharmacol Exp Ther, 337 (3): 822-9. [PMID:21421741]

236. Sun B, Schally AV, Halmos G. (2000) The presence of receptors for bombesin/GRP and mRNA for three receptor subtypes in human ovarian epithelial cancers. Regul Pept, 90 (1-3): 77-84. [PMID:10828496]

237. Sun YG, Chen ZF. (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature, 448 (7154): 700-3. [PMID:17653196]

238. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. (2009) Cellular basis of itch sensation. Science, 325 (5947): 1531-4. [PMID:19661382]

239. Sunaga N, Tsuchiya S, Minato K, Watanabe S, Fueki N, Hoshino H, Makimoto T, Ishihara S, Saito R, Mori M. (1999) Serum pro-gastrin-releasing peptide is a useful marker for treatment monitoring and survival in small-cell lung cancer. Oncology, 57 (2): 143-8. [PMID:10461062]

240. Sunday ME, Yoder BA, Cuttitta F, Haley KJ, Emanuel RL. (1998) Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia. J Clin Invest, 102 (3): 584-94. [PMID:9691095]

241. Swain MG. (2008) Gastrin-releasing peptide and pruritus: more than just scratching the surface. J Hepatol, 48 (4): 681-3. [PMID:18280606]

242. Takada M, Kusunoki Y, Masuda N, Matui K, Yana T, Ushijima S, Iida K, Tamura K, Komiya T, Kawase I et al.. (1996) Pro-gastrin-releasing peptide (31-98) as a tumour marker of small-cell lung cancer: comparative evaluation with neuron-specific enolase. Br J Cancer, 73 (10): 1227-32. [PMID:8630283]

243. Tan YR, Qi MM, Qin XQ, Xiang Y, Li X, Wang Y, Qu F, Liu HJ, Zhang JS. (2006) Wound repair and proliferation of bronchial epithelial cells enhanced by bombesin receptor subtype 3 activation. Peptides, 27 (7): 1852-8. [PMID:16426703]

244. Tan YR, Qin XQ, Xiang Y, Yang T, Qu F, Wang Y, Liu HJ, Weber HC. (2007) PPARalpha and AP-2alpha regulate bombesin receptor subtype 3 expression in ozone-stressed bronchial epithelial cells. Biochem J, 405 (1): 131-7. [PMID:17355223]

245. Toi-Scott M, Jones CL, Kane MA. (1996) Clinical correlates of bombesin-like peptide receptor subtype expression in human lung cancer cells. Lung Cancer, 15 (3): 341-54. [PMID:8959679]

246. Tokita K, Hocart SJ, Coy DH, Jensen RT. (2002) Molecular basis of the selectivity of gastrin-releasing peptide receptor for gastrin-releasing peptide. Mol Pharmacol, 61 (6): 1435-43. [PMID:12021405]

247. Tokita K, Hocart SJ, Katsuno T, Mantey SA, Coy DH, Jensen RT. (2001) Tyrosine 220 in the 5th transmembrane domain of the neuromedin B receptor is critical for the high selectivity of the peptoid antagonist PD168368. J Biol Chem, 276 (1): 495-504. [PMID:11013243]

248. Tokita K, Katsuno T, Hocart SJ, Coy DH, Llinares M, Martinez J, Jensen RT. (2001) Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor. J Biol Chem, 276 (39): 36652-63. [PMID:11463790]

249. Uehara H, González N, Sancho V, Mantey SA, Nuche-Berenguer B, Pradhan T, Coy DH, Jensen RT. (2011) Pharmacology and selectivity of various natural and synthetic bombesin related peptide agonists for human and rat bombesin receptors differs. Peptides, 32 (8): 1685-99. [PMID:21729729]

250. Valentine JJ, Nakanishi S, Hageman DL et al. (1992) CP-70,030 and CP-75,998: the first non-peptide antagonists of bombesin and gastrin-releasing peptide. Bioorg Med Chem Lett, 2: 333-338.

251. Varga G, Reidelberger RD, Liehr RM, Bussjaeger LJ, Coy DH, Solomon TE. (1991) Effects of potent bombesin antagonist on exocrine pancreatic secretion in rats. Peptides, 12 (3): 493-7. [PMID:1717952]

252. Von Schrenck T, Heinz-Erian P, Moran T, Mantey SA, Gardner JD, Jensen RT. (1989) Neuromedin B receptor in esophagus: evidence for subtypes of bombesin receptors. Am J Physiol, 256 (4 Pt 1): G747-58. [PMID:2539739]

253. von Schrenck T, Wang LH, Coy DH, Villanueva ML, Mantey S, Jensen RT. (1990) Potent bombesin receptor antagonists distinguish receptor subtypes. Am J Physiol, 259 (3 Pt 1): G468-73. [PMID:2169207]

254. Wada E, Way J, Lebacq-Verheyden AM, Battey JF. (1990) Neuromedin B and gastrin-releasing peptide mRNAs are differentially distributed in the rat nervous system. J Neurosci, 10: 2917-2930. [PMID:2398368]

255. Wada E, Way J, Shapira H, Kusano K, Lebacq-Verheyden AM, Coy D, Jensen R, Battery J. (1991) cDNA cloning, characterization, and brain region-specific expression of a neuromedin-B-preferring bombesin receptor. Neuron, 6 (3): 421-30. [PMID:1848080]

256. Wang LH, Battey JF, Wada E, Lin JT, Mantey S, Coy DH, Jensen RT. (1992) Activation of neuromedin B-preferring bombesin receptors on rat glioblastoma C-6 cells increases cellular Ca2+ and phosphoinositides. Biochem J, 286 ( Pt 2): 641-8. [PMID:1326946]

257. Wang LH, Coy DH, Taylor JE, Jiang NY, Moreau JP, Huang SC, Frucht H, Haffar BM, Jensen RT. (1990) des-Met carboxyl-terminally modified analogues of bombesin function as potent bombesin receptor antagonists, partial agonists, or agonists. J Biol Chem, 265 (26): 15695-703. [PMID:1697594]

258. Wang LH, Mantey SA, Lin JT, Frucht H, Jensen RT. (1993) Ligand binding, internalization, degradation and regulation by guanine nucleotides of bombesin receptor subtypes: a comparative study. Biochim Biophys Acta, 1175 (2): 232-42. [PMID:8380344]

259. Wang QJ, Knezetic JA, Schally AV, Pour PM, Adrian TE. (1996) Bombesin may stimulate proliferation of human pancreatic cancer cells through an autocrine pathway. Int J Cancer, 68 (4): 528-34. [PMID:8945626]

260. Weber D, Berger C, Eickelmann P, Antel J, Kessler H. (2003) Design of selective peptidomimetic agonists for the human orphan receptor BRS-3. J Med Chem, 46 (10): 1918-30. [PMID:12723954]

261. Weber D, Berger C, Heinrich T, Eickelmann P, Antel J, Kessler H. (2002) Systematic optimization of a lead-structure identities for a selective short peptide agonist for the human orphan receptor BRS-3. J Pept Sci, 8 (8): 461-75. [PMID:12212809]

262. Weber HC, Hampton LL, Jensen RT, Battey JF. (1998) Structure and chromosomal localization of the mouse bombesin receptor subtype 3 gene. Gene, 211: 125-131. [PMID:9573346]

263. Whitley JC, Moore C, Giraud AS, Shulkes A. (1999) Molecular cloning, genomic organization and selective expression of bombesin receptor subtype 3 in the sheep hypothalamus and pituitary. J Mol Endocrinol, 23 (1): 107-16. [PMID:10425452]

264. Wood SM, Jung RT, Webster JD, Ghatei MA, Adrian TE, Yanaihara N, Yanaihara C, Bloom SR. (1983) The effect of the mammalian neuropeptide, gastrin-releasing peptide (GRP), on gastrointestinal and pancreatic hormone secretion in man. Clin Sci, 65 (4): 365-71. [PMID:6349902]

265. Wu JM, Nitecki DE, Biancalana S, Feldman RI. (1996) Discovery of high affinity bombesin receptor subtype 3 agonists. Mol Pharmacol, 50 (5): 1355-63. [PMID:8913368]

266. Xiao D, Wang J, Hampton LL, Weber HC. (2001) The human gastrin-releasing peptide receptor gene structure, its tissue expression and promoter. Gene, 264 (1): 95-103. [PMID:11245983]

267. Xu Y, Jiang YF, Wu B. (2012) New agonist- and antagonist-based treatment approaches for advanced prostate cancer. J Int Med Res, 40 (4): 1217-26. [PMID:22971474]

268. Yamada K, Ohki-Hamazaki H, Wada K. (2000) Differential effects of social isolation upon body weight, food consumption, and responsiveness to novel and social environment in bombesin receptor subtype-3 (BRS-3) deficient mice. Physiol Behav, 68 (4): 555-61. [PMID:10713297]

269. Yamada K, Santo-Yamada Y, Wada E, Wada K. (2002) Role of bombesin (BN)-like peptides/receptors in emotional behavior by comparison of three strains of BN-like peptide receptor knockout mice. Mol Psychiatry, 7 (1): 113-7, 6. [PMID:11803457]

270. Yamada K, Santo-Yamada Y, Wada K. (2002) Restraint stress impaired maternal behavior in female mice lacking the neuromedin B receptor (NMB-R) gene. Neurosci Lett, 330 (2): 163-6. [PMID:12231437]

271. Yamada K, Santo-Yamada Y, Wada K. (2003) Stress-induced impairment of inhibitory avoidance learning in female neuromedin B receptor-deficient mice. Physiol Behav, 78 (2): 303-9. [PMID:12576129]

272. Yamada K, Wada E, Imaki J, Ohki-Hamazaki H, Wada K. (1999) Hyperresponsiveness to palatable and aversive taste stimuli in genetically obese (bombesin receptor subtype-3-deficient) mice. Physiol Behav, 66 (5): 863-7. [PMID:10405115]

273. Yang HJ, Gu Y, Chen C, Xu C, Bao YX. (2011) Diagnostic value of pro-gastrin-releasing peptide for small cell lung cancer: a meta-analysis. Clin Chem Lab Med, 49 (6): 1039-46. [PMID:21649553]

274. Yu Z, Ananias HJ, Carlucci G, Hoving HD, Helfrich W, Dierckx RA, Wang F, de Jong IJ, Elsinga PH. (2013) An update of radiolabeled bombesin analogs for gastrin-releasing peptide receptor targeting. Curr Pharm Des, 19 (18): 3329-41. [PMID:23431995]

275. Zhang H, Abiraj K, Thorek DL, Waser B, Smith-Jones PM, Honer M, Reubi JC, Maecke HR. (2012) Evolution of bombesin conjugates for targeted PET imaging of tumors. PLoS ONE, 7 (9): e44046. [PMID:23024746]

276. Zhang L, Parks GS, Wang Z, Wang L, Lew M, Civelli O. (2013) Anatomical characterization of bombesin receptor subtype-3 mRNA expression in the rodent central nervous system. J Comp Neurol, 521 (5): 1020-39. [PMID:22911445]

277. Zhang Q, Bhola NE, Lui VW, Siwak DR, Thomas SM, Gubish CT, Siegfried JM, Mills GB, Shin D, Grandis JR. (2007) Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. Mol Cancer Ther, 6 (4): 1414-24. [PMID:17431120]

278. (1988) Bombesin-like peptides in health and disease. Proceedings of an international symposium. October 13-16, 1987, Rome, Italy. A tribute to Vittorio Erspamer, M.D. Ann NY Acad Sci, 547: 1-541. [PMID:3071214]