The tachykinin receptors exert their effects through the binding of guanine nucleotide-binding regulator proteins (G-proteins). There are three tachykinin receptors; NK₁, NK₂, and NK₃, and each has a preferred ligand; substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), respectively. More than 40 tachykinin peptide ligands have been identified in both mammalian and submammalian species, all of which share the common C-terminal sequence Phe-X- Gly-Leu-Met and which accounts for their biological function. The term tachykinin was originally used to identify SP because it produced spasmodic effects in various intestinal smooth muscle cells. Tachy is Greek for rapid and Kinin is Greek for set in motion. Together these terms described the rapid contraction of smooth muscle treated with SP. Tachykinins are widely distributed in the central nervous system, however, their expression patterns are distinct. SP and NKA are produced from the same mRNA transcript and primarily have overlapping expression patterns in structures implicated in regulation of behavioral processes, such as the amygdala. NK₁ and NK₃ are widely distributed in the central nervous system, while NK₂ is localized in the smooth muscle of the gastrointestinal, respiratory, and urinary tracts and some discrete regions of the CNS such as the prefrontal cortex and the hippocampus.

Tachykinin receptors are composed of an extracellular amino terminus, seven transmembrane domains followed by an intracellular carboxyl terminus. Ligand binding results in the mobilization of calcium, the activation of phospholipase C, the hydrolysis of PIP₂ into second messengers IP₃ and diacylglycerol, and the inhibition of cAMP synthesis. In addition, tachykinin receptors have also been shown to regulate the functions of other neurotransmitters such as serotonin and dopamine. Receptor signaling is terminated when the ligand-bound receptor is internalized and both peptide and receptor are broken down enzymatically.

Pharmacological or genetic manipulation of the tachykinin receptor pathways modulates anxiety, depression, and schizophrenia related behavior in animal studies; however, antagonists tested to date have not proved efficacious in clinical trials. The reason for these results may lie in the differences in receptor expression between humans and animal models used in preclinical testing, the ADME profile of the drugs (Adsorption, Distribution, Metabolism, and Excretion), the presence of overlapping function among various tachykinin receptors and the fact that several different ligands can bind to the same receptor with variable affinities, or some as yet undetermined factor. Additionally, drug action may vary due to inter-individual variation and drug-drug interactions. So far the only neurokinin antagonist licensed by the US-FDA is aprepitant, an NK₁ receptor antagonist approved for the treatment of chemotherapy-induced nausea and vomiting (CINV/Emesis). The entries for each tachykinin receptor identify receptor specific antagonists; however, several research laboratories have identified dual and triple receptor antagonists for the treatment of gastrointestinal and psychological diseases as well as pain sensitivity. These antagonists may play a role in regulating tachykinin-mediated contraction where expression of individual tachykinin receptor types over lap and the condition may be controlled by more than one tachykinin receptor.

Tachykinin 1 Receptor

Description: Tachykinin 1 (NK₁) receptor is a member of the tachykinin receptor family, which is characterized by the ability to bind tachykinin neuropeptides resulting in spasmodic contractions of various tissue types. NK₁ receptor is a seven transmembrane receptor that associates with the G-protein q11. It is the most studied neurokinin receptor. NK₁ receptor is the only tachykinin receptor known to have two isoforms, full-length and truncated due to alternative splicing. The expression of each of these isoforms varies with different tissues as well as under different environmental conditions. The truncated form lacks the G-protein binding domain and therefore displays diminished calcium signaling compared to the full-length form.

Agonists: Substance P is the most selective agonist towards NK₁; however, other endogenous agonists, such as neurokinin A (NKA) and NKB, have weak binding efficiency. Several peptide agonists have been designed based on modifications to endogenous SP. Additionally, several non-peptide antagonists have been designed based on the presence of structural features shared with peptide antagonists that were important for interaction with the receptor.

Tissue Localization: NK₁ is widely distributed in both the central nervous system and peripheral tissues including the substantia nigra, the hypothalamus, the lateral habenula, the inferior colliculus the central amygdale, the frontal cortex and the sensorimotor cortex as well as the gastrointestinal tract. The presence of NK₁ receptor in CNS structures implicated in emotional processes has fueled much investigation into modulation of this pathway for the treatment of numerous psychological disorders such as social anxiety disorder, major depression disorder, general anxiety disorder, post-traumatic stress disorder, and schizophrenia. It also plays a role in the perception of visceral pain sensitivity. NK1 receptor is also known to modulate the activity of other neurotransmitters at the neural synapse such as serotonin and dopamine. Furthermore, NK₁ receptor expression increases in malignant cells and up-regulates HIV-1 infection. It also induces the polarization of T-helper subsets of cells, indicating that specific antagonists may prevent infection and inflammation.

Physiology: The ligand for NK₁ receptor, SP, was the first tachykinin peptide identified due to its ability to stimulate contraction of isolated rabbit jejunum. The truncated form of NK₁ receptor has been linked to breast cancer and may induce the induction of the TAC1 gene, resulting in cell autonomous proliferation. In studies of colitis patients, the expression of truncated NK₁ receptor increased as the subjects transitioned to malignant transformation. This finding suggests that targeting the NK₁ receptor could prevent inflammation-induced transformation.

Antagonists: Since the discovery of CP-96,345 by Pfizer in 1991 there have been over 300 patents files for the use of NK₁ antagonists. Currently only two tachykinin antagonists have been licensed by the FDA: aprepitant (MK0869;Emend) and its pro-drug fosaprepitant for post operative/chemotherapy-induced nausea and vomiting (CINV/Emesis). Several antagonists have been used in phase IIb/III clinical trials, however, to date, no NK₁ receptor antagonists have been licensed for use in the treatment of indications such as psychological disorders, irritable bowel syndrome, or asthma.

Tachykinin 2 Receptor

Description; Tachykinin 2 (NK₂) receptor is a member of the tachykinin receptor family, which is characterized by the ability to bind tachykinin neuropeptides resulting in rapid movement or “spasmodic contractions” of various tissue types. The NK₂ receptor is a seven transmembrane receptor that associates with the G-proteins G_s and G_q/G₁₁. In the presence of ligand, NK₂ receptor coupled to (G-protein) results in stimulation of inositol monophosphate, activation of phospholipase C, and inhibition of cyclic AMP.

Agonists: NK2 receptor preferentially binds its ligand neurokinin A (NKA). NK₂ receptor can also bind the NK₁ and NK₃ receptor ligands, substance P and NKB respectively; however, the affinity for these ligands is much lower than for NKA. Elongated forms of NKA called neuropeptide K (NPK) and NP-gamma also activate NK₂ receptor with similar kinetics to NKA [4].

Tissue Localization; The localization, sequence and function of NK₂ receptors vary between species [3]. NK₂ receptor is widely expressed in the smooth muscle of the gastrointestinal, respiratory, and urinary tracts and to a much lesser extent in some discrete regions of the CNS such as the prefrontal cortex and the hippocampus [1].

Physiology: The stimulation of tachykinin receptors leads to activation of phospholipase C and elevation of intracellular calcium levels. Unlike NK₁ and NK₃, blockade of NK₂ does not affect basal levels of neurotransmitters that mediate the stress response; however, it does diminish the firing of neurons in the prefrontal cortex. Tachykinins are important in mediating smooth muscle contraction and relaxation, vasodilation, and activation of the immune system. Additionally, NK₂ receptor plays notable roles in visceral pain sensitivity and modulating intestinal motility.

Antagonists: Due to the fact that NK₂ receptors are significantly expressed in the gastrointestinal, respiratory, and urinary tracts, therapeutic indications for NK₂ receptor antagonists include irritable bowel syndrome, asthma, infant colitis, and post-operative ileus. NK₂ receptor antagonists are also being investigated for the treatment of depression and anxiety. NK₂ antagonists typically fall into two categories; peptide and non-peptide. Peptide-based antagonists are usually generated by amino acid substitution of the endogenous tachykinin receptor agonists SP, NKA and NKB. Additionally, chemical modifications are done to create structural rigidity; however, pre-clinical testing showed these compounds had low specificity and bioavailability. Two of the best studied NK₂ antagonists are sardutant (SR48968) and nepadutant (MEN11420). NK₂ antagonist, sardutant, was tested in phase IIb/III clinical trials for treatment of major depressive disorder. The results showed moderate short-term benefits and the drug was well-tolerated, unlike some anti-depressants currently in use. DNK-333, an NK₁/NK₂ dual receptor antagonist, was also tested in clinical trials and relieved symptoms associated with irritable bowel syndrome.

Tachykinin 3 Receptor

Description: Tachykinin 3 (NK₃) receptor is a member of the tachykinin receptor family, which is characterized by the ability to bind tachykinin neuropeptides resulting in rapid movement or “spasmodic contractions” of various tissue types. Like all tachykinin receptors, NK₃ receptor is a seven transmembrane receptor that associates with the G-proteins q11. In the presence of ligand, NK₃ receptor coupled to (G-protein) results in stimulation of inositol monophosphatate, activation of phospholipase C, formation cyclic AMP accumulation and release of intracellular Ca²⁺ reserves [2-3].

Agonists: NK₃ receptor preferentially binds its ligand neurokinin B (NKB) as well as several agonists including, senktide (selective neurokinin B receptor peptide) and [Met-Phe7]-NKB, a modified version of the NKB ligand. NK₃ receptor can also bind the NK₁ and NK₂ receptor ligands, substance P and NKA respectively; however, the affinity for these ligands is much lower than for NKB.

Tissue Localization: The localization, sequence and function of NK₃ receptors vary between species [3]. NK₃ receptors are found throughout both the central and peripheral nervous system. In humans, NK₃ receptors are located in the frontal, temporal and parietal cortices, the hippocampus, the locus niger, the dorsal raphe nucleus, the hypothalamus, the striatum, the kidney, total human embryo, and the placenta. In the rat NK₃ is found in the portal vein and this tissue is the preferred tissue for assay of NK₃ receptors as guinea pig ileum, another frequently used model tissue, often contains NK₁ receptors as well. NK₃ can also be found in the rat mid-cortical layers, the supra-optic nucleus, the zona incerta, the amygdale, the substantia nigra pars compacta, the ventral tegumental area, the hippocampus, and the hypothalamus. The guinea pig is also commonly used to study tachykinin signaling as receptor expression more accurately mimics the tissue distribution of the receptors in humans than rats do.

Physiology: The stimulation of tachykinin receptors leads to activation of phospholipase C and elevation of intracellular calcium levels. Activation of the NK₃ receptor modulates the activity and release of other neurotransmitters such as dopamine and norepinephrine. Tachykinins are important in mediating smooth muscle contraction and relaxation, vasodilation, and activation of the immune system. The role of NK₃ receptor in the CNS has not been fully elucidated but it is believed to play a role in somatic and visceral sensory integration, cardio-respiratory regulation, water and electrolyte balance, and may be important in learning, memory, and behavioral responses. NK₃ receptor may play a role in the pathogenesis of obstructive airway disease, hypertension, pre-eclampsia, irritable bowel syndrome, pain perception, schizophrenia and anxiety and depression. The therapeutic potential of several NK₃ receptor antagonists are being investigated, especially for their use as anti-anxiolytic and anti-depressant therapies.

Antagonists: NK₃ antagonists typically fall into two categories; peptide and non-peptide. Peptide-based antagonists are usually generated by amino acid substitution of the endogenous tachykinin receptor agonists SP, NKA and NKB. Additionally, chemical modifications are done to create structural rigidity; however, pre-clinical testing showed these compounds had low specificity and bioavailability. Two of the best studied non-peptide antagonists are osanetant (SR142801) and talnetant (SB223412), which were both investigated in clinical trials before investigation was discontinued by the pharmaceutical companies.

1. Altamura M. (2012) Tachykinin NK2 receptor antagonists. A patent review (2006 - 2010). Expert Opin Ther Pat, 22 (1): 57-77. [PMID:22149761]

2. Oury-Donat F, Carayon P, Thurneyssen O, Pailhon V, Emonds-Alt X, Soubrié P, Le Fur G. (1995) Functional characterization of the nonpeptide neurokinin3 (NK3) receptor antagonist, SR142801 on the human NK3 receptor expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther, 274 (1): 148-54. [PMID:7616392]

3. Simonsen KB, Juhl K, Steiniger-Brach B, Nielsen SM. (2010) Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications. Curr Opin Drug Discov Devel, 13 (4): 379-88. [PMID:20597024]

4. van Giersbergen PL, Shatzer SA, Burcher E, Buck SH. (1992) Comparison of the effects of neuropeptide K and neuropeptide gamma with neurokinin A at NK2 receptors in the hamster urinary bladder. Naunyn Schmiedebergs Arch Pharmacol, 345 (1): 51-6. [PMID:1311427]