General

Adrenoceptors (AR) are a group of nine 7-transmembrane receptors comprising 3 main types, α₁, α2 and β, each with 3 subtypes that mediate the central and peripheral actions of the catecholamine hormones and neurotransmitters adrenaline (epinephrine) and noradrenaline (norepinephrine). Adrenoceptors are found in nearly all peripheral tissues and on many neuronal populations within the central nervous system. Both noradrenaline and adrenaline play important roles in the control of blood pressure, myocardial contractile rate and force, airway reactivity, and a variety of metabolic and central nervous system functions. Both catecholamines activate all adrenoceptor subtypes although noradrenaline displays some selectivity for β₁-AR and adrenaline for β₂-AR due to slightly higher affinity at their respective subtypes. Adrenaline and noradrenaline are important in the "fight or flight response" where blood is diverted from non-essential organs such as skin and gut to skeletal muscle, whilst maximising cardiac output, oxygenation and serum glucose and uptake into muscle. Thus, endogenous agonist actions at α₁-AR increase vascular smooth muscle contraction in those blood vessels where these predominate and relaxation in blood vessels where β-ARs predominate. Stimulation of β-ARs in the heart increases heart rate and contractility and actions on β₁-ARs on the juxta-glomerular apparatus in the kidney increases renin release. Stimulation of β₂-AR in airways causes smooth muscle relaxation and bronchodilation. Activation of β₂-AR also has other effects - tremor in skeletal smooth muscle and metabolic actions including a decrease is serum potassium, calcium, magnesium, phosphate, growth hormone, an increase in lactate, renin and lipolysis, and increased serum glucose due to breakdown of glycogen in the liver to release glucose as well as increasing glucose uptake into skeletal muscle. The only known relevant effect of β₃-AR stimulation in adult humans is relaxation of smooth muscle in the urinary bladder.
The physiological agonists noradrenaline and adrenaline have some clinical uses: both are used to raise blood pressure in shock (septic or cardiogenic) and adrenaline is used to treat anaphylaxis and cardiac arrest. More selective agonists and antagonists interacting with adrenoceptors have proved useful in the treatment of a variety of diseases, including arrhythmias, ischaemic heart disease (post-myocardial infarction and angina pectoris), hypertension, portal hypertension, congestive heart failure, asthma, depression, benign prostatic hyperplasia, glaucoma, sedation, thyrotoxicosis, migraine and anxiety. Drugs acting at these receptors are also useful in several other therapeutic situations including premature labour (no-longer used) and opioid withdrawal, and as adjuncts to general anaesthetics.

Discovery of adrenaline and adrenoceptors
Oliver and Schäfer discovered in 1894 that ingestion of sheep adrenal gland caused adrenaline-mediated vasoconstriction of the radial artery, rapidly followed by more widespread vasoconstriction, increased blood pressure and ventricular contraction [114-115]. Subsequently, adrenaline was isolated as a pure crystalline substance [162], its formula determined in 1901 and it was named to distinguish it from other less active isolates from adrenal medulla. Adrenaline was first used clinically in 1903 in patients with asthma [25-26]. Sir Henry Dale pioneered the development of drugs acting selectively at adrenoceptors (ARs) and recognised that the actions of adrenaline were altered by preexposure to ergotoxine from a vasoconstrictor to a vasodilator response that indicated a mixed response under normal conditions. He suggested that ergotoxine caused a selective paralysis of myoneural junctions responsible for the vasoconstrictor response [40].
The history of the recognition of adrenoceptor subtypes began in 1948, with the division into two major types, α and β, based on their pharmacological characteristics (i.e., rank order of potency of agonists) [3]. Subsequently, both the α and β types were subdivided into α₁, α₂, β₁ and β₂ subtypes (for a more complete historical perspective, see [29]. Based on more recent pharmacological and molecular evidence, it is now clear that classification is based on three major types - α₁, α₂ and β - each of which is further divided into three subtypes [27].

α₁-Adrenoceptors

α₁-adrenoceptor subtypes
Building on an initial report that both phentolamine and WB 4101 inhibited [³H]prazosin binding in rat frontal cortex in a manner consistent with more than one type of receptor [16], Morrow and Creese [105] formally proposed a definition of α_1A and α_1B ARs based on the differential affinities of WB 4101 and phentolamine. At about the same time Johnson and Minneman [75] observed that the alkylating agent chloroethylclonidine selectively inactivated only half of the HEAT (BE2254) binding to α₁-ARs in rat cerebral cortex. The inactivated sites corresponded to the α_1B-AR subtype, based on low affinity for WB 4101 [68,104].
Three α₁-AR subtypes have been identified by cloning and are now known as α_1A, α_1B and α_1D. The α_1B-AR from the DDT cell line (hamster smooth muscle) was cloned first [37], followed by what was thought to be a novel α₁-AR from a bovine brain cDNA library identified as the α_1C subtype [142]. Subsequently, it was shown that this clone is a species orthologue corresponding to the pharmacologically defined α_1A subtype [57,70]. A third α₁-AR was cloned from rat cortex and initially designated as an α_1A-AR [94]. However, an identical recombinant rat α₁-AR subtype was independently identified by Perez et al. [120] and denoted as the α_1D-AR. This α_1D-subtype was subsequently characterized functionally in tissues [81,122]. It appears that the α_1D-AR signals less effectively upon agonist stimulation as compared to the other subtypes, perhaps because it exhibits spontaneous internalization [101].
Four isoforms of the α_1A-AR have been reported. In addition to the originally reported sequence (α_1A-1), two C-terminal variants (α_1A-2 and α_1A-3) produced by alterative splicing were reported in 1995 [71]. An additional splice variant (α_1A-4) was subsequently reported [32]. No functional differences among these splice variants have been reported to date.
A fourth α₁-AR subtype was postulated and designated as α_1L based on low affinity for prazosin [116] and RS-17053. The evidence for the existence of the α_1L-AR was supported by pharmacological data in several tissues, including human prostate, bladder neck and periurethral longitudinal muscle [55,106]. There is now strong evidence that the α_1L subtype represents a particular conformational state of the α_1A-AR [56] or due to differences in characteristics dependent on the tissue or assay environment [37].The α_1L-AR mediated responses in the mouse prostate are essentially abolished in α_1A-AR knockout mice [66].

α₁-adrenoceptor expression
α₁-AR are expressed in blood vessels, heart, urinary tract, brain, kidney and liver [29,56,64,103,111,123,128]. The individual subtypes have clearly defined roles in the brain, cardiovascular system and genitourinary system. In the brain, α_1A-AR stimulation increases neurogenesis, learning and memory and improves mood whereas α_1B-AR activation improves memory consolidation, exploratory activity and causes behavioural activation [4]. In the cardiovascular system α_1A-AR have a dominant role in small densely innervated arteries in contrast to α_1D-AR that are involved in contraction of large poorly innervated arteries and cause vessel hypertrophy [4]. In the heart, α_1A-AR are protective and adaptive whereas α_1B-AR activation causes maladaptive hypertrophy [4,111]. The dominant α-AR subtype in the genitourinary system is the α_1A-AR that mediates contraction in the ureter, bladder, urethra and prostate but is also involved in fertility in the male [158].

α₁-adrenoceptor signalling
The α₁-ARs couple primarily to G_αq-proteins to promote calcium release and inositol phosphate production and also activate protein kinase C and mitogen activated protein kinases. Of the subtypes, α_1A-ARs couple most efficiently to these pathways. α_1A- and α_1B-ARs can also couple to adenylyl cyclase to increase cAMP but with lower coupling efficacy [39,128].
The crystal structure of the α_1B-AR has recently been determined [42].

Selectivity and clinical uses of drugs acting at α₁-adrenoceptors
Agonists
The general α₁-AR agonist phenylephrine is a common constituent of orally and nasally administered medicines for symptomatic relief of colds, coughs, influenza, allergies, sinusitis and bronchitis but can produce many side effects including increased blood pressure, dizziness, headache and tachycardia [4]. Oxymetazoline and xylometazoline (that display some α_1A-AR selectivity but are complicated by significant actions at α₂-AR and 5HT_1B receptors [39], are also used as over-the-counter remedies for nasal congestion. The agonist A61603 is highly selective for the α_1A-AR [39,52,128] although not used clinically. There are no selective agonists for α_1B- or α_1D-AR.

Antagonists
Non-selective α₁-AR antagonists (e.g. doxazosin) are used to treat arterial hypertension. They are also useful for improving symptoms in benign prostatic hyperplasia (e.g. tamsulosin, terazosin). Prazosin, and increasingly doxazosin, are used to help symptoms in PTSD. Phentolamine and phenoxybenzamine (which has an ability to covalently bind to α₁-AR making it "irreversible" [58]) are used to treat phaeochromocytoma. Labetalol is the drug of choice for hypertension in pregnancy. Several antidepressants and anti-psychotics have high α_1A-AR affinity that may partly account for their blood pressure lowering side effects.
Several α_1A-AR selective antagonists are available (e.g. silodosin, S(+)-niguldipine, SNAP5089, RS-100329 and Ro-70-0004) and are selective for α_1A-ARs over the α_1B- and α_1D-AR subtypes [159]. The insurmountable antagonist ρ-Da1a is also α_1A-AR subtype selective. There are no selective antagonists for α_1B-AR. BMY-7378 shows selectivity for α_1D-AR [129].
Both agonist and antagonist pharmacological characteristics are relatively well preserved across species.

α₂-Adrenoceptors

α₂-adrenoceptor subtypes
The evidence for α₂-AR subtypes originally came from binding and functional studies in various tissues and cell lines, and more recently from cells transfected with the cDNA for the receptors . On the basis of these studies, three genetically distinct α₂-AR subtypes have been defined- α_2A, α_2B and α_2C. The α_2A-AR, at which prazosin has a relatively low affinity and oxymetazoline a relatively high affinity, is found in for example in human platelets and HT29 cells [27,84]. The second subtype, α_2B, was identified in neonatal rat lung and in NG108 cells [30]. This subtype has relatively high affinity for prazosin and a low affinity for oxymetazoline [30,156]. A third subtype, α_2C, was originally identified in an opossum kidney (OK) cell line and subsequently cloned from human kidney [107,131]. This subtype also has relatively high affinity for prazosin and a low affinity for oxymetazoline, but is pharmacologically distinct from the α_2B subtype [20]. The α_2D, that was described in the rat salivary [98] and bovine pineal gland [144] and cloned from the rat [88] are species orthologues of the human α_2A subtype. The species orthologue of the human α_2A-ARs found in the rat, mouse and cow has significantly different antagonist pharmacology, but the agonist pharmacology appears to be similar.
Additional α₂-AR subtypes have been identified in fish, including five receptor genes in the zebrafish and as many as eight in the pufferfish [134]. In the zebrafish, three of the subtypes are similar to those found in mammals (orthologues, the same gene in different species), whereas the other two are not found in mammals, but are paralogues (duplicated genes in the same species). The significance of the numerous receptor subtypes in non-mammalian species is not well understood [28].

α₂-adrenoceptor expression
α₂-AR are widely distributed in the brain and in the periphery [47,51,90,95,121]. Although originally identified and regarded as prejunctional autoreceptors (i.e. receptors on presynaptic neurones that when stimulated by noradrenaline in the synapse act as a negative feedback mechanism inhibiting further noradrenaline release from the neurone), it rapidly became evident that α₂-AR are located both pre and post-junctionally [18]. α_2A-AR are located in the locus coeruleus and other noradrenergic cell bodies involved in controlling sympathetic outflow, brainstem, cerebral cortex, hippocampus, septum, hypothalamic and amygdaloid nuclei and spinal cord [95]. α_2C-AR are largely located in caudate putamen, olfactory tubercle, hippocampus and cerebral cortex [95]. More recent detailed studies in human prefrontal cortex show that the dominant (87%) receptors are post-synaptic α_2A-AR, with the remaining α_2C-AR (13%) being located both pre and post-synaptically (60/40) [51]. α_2B-AR are weakly expressed solely in the thalamus [51]. All three α₂-AR subtypes are widely distributed in the periphery being present in the heart, blood vessels, lung, kidney, pancreas, gastrointestinal tract, adrenal gland, spleen and platelets [47,121,126].

α₂-adrenoceptor signalling
α₂-AR are primarily G_i/G_o coupled receptors, so that activation of α₂-AR causes an inhibition of adenylyl cyclase, inhibition of L-type voltage-gated Ca²⁺ channels (thus raising intracellular calcium), increased Na⁺/H⁺ exchange and opening K⁺ channels (K-ATP), stimulate phospholipase α₂ and ERK1/2 phosphorylation [92,95]. In some circumstances α_A2- and α_2B-AR can also couple to G_αs to increase adenylyl cyclase activity and cAMP accumulation [46,48], although this G_αs-coupling requires high receptor expression, high concentrations of high efficacy agonists and is of lower coupling efficacy. The physiological significance of this mechanism is unknown [127]. α-AR are important for control of blood pressure, analgesia, sedation, platelet aggregation and hypothermia [129].
The structures of the three α₂-AR subtypes have recently been determined [33,130,163].

Selectivity and clinical uses of drugs acting at α₂-adrenoceptors
Agonists
The α₂-AR subtypes are activated by the endogenous ligands, (-)-adrenaline and (-)-noradrenaline but no known clinical actions are associated with these effects. The non-selective partial agonist clonidine was one of the first selective α₂-AR agonists to be developed and is a centrally acting anti-hypertensive that alters baroreflex control to cause hypotension and bradycardia [74,119,124]. These properties are shared by other α₂-AR partial agonists, e.g. dexmedetomidine and xylazine. These compounds, particularly dexmedetomidine, a very potent α₂-AR agonist, are now mainly used for sedation in an intensive care setting including as an adjunct to other agents as it causes less respiratory depression and is useful for reducing delirium, nausea and agitation, and even allows arousal or cooperative sedation allowing neurosurgery in awake patients [60,63,89,154]. It is also useful for minimising withdrawal symptoms from opioids, benzodiazepines, alcohol and nicotine. The activity of dexmedetomidine at α₂-ARs is mainly associated with its affinity for all three α₂-AR subtypes [127] but it and similar drugs may also be used to control agitation associated with schizophrenia or bipolar disorder. Xylazine has been used in veterinary medicine for >50 years for its analgesic and sedative effects in a variety of species including cats, dogs and horses but has been superseded to some extent by dexmedetomidine which is more potent. An important advantage conferred by these compounds is that the sedation associated with their use is easily reversible [15]. Brimonidine (UK14304) (UK14304) is a non-selective full agonist that has vasoconstrictor and anti-inflammatory properties that make it useful for the treatment of facial erythema in rosacea and glaucoma where it reduces aqueous humour production whist increasing its outflow [2,74,119,124-125]. Guanabenz is a partial agonist that displays some α_2A-AR selectivity but also activates α_2B-AR and has no agonist actions at α_2C-AR although it has affinity for this subtype [74]. It is used mainly as a centrally acting anti-hypertensive perhaps reflecting its actions on the two dominant α₂-AR subtypes in the CNS. Guanfacine, another partial agonist at all 3 α₂-AR subtypes, is again somewhat α_2A-AR selective, and is mainly used in patients with ADHD as it avoids the cardiovascular and hypertensive issues of other ADHD medications [87,110]. Lofexidine is now used predominantly to treat the symptoms of opiate withdrawal [151]. It has an interesting pharmacological profile appearing in GTPγs binding assays to be a selective agonist at α_2B-AR yet in binding studies displaying high affinity for all 3 subtypes [44,74]. Among other agonists active at α₂-ARs, tizanidine is used to relieve muscle spasticity [63], brimonidine (UK14304) is used for glaucoma where it reduces aqueous humour production whilst increasing its outflow [2], and brimonidine and oxymetazoline are used as topical vasoconstrictors in rosacea [113]. Several anti-Parkinsonian drugs such as lisuride, roxindole and terguride have high potency competing for α₂-AR binding [101]. The agonist xylazine has recently emerged in the North American illegal drug markets as a common admixture with synthetic opioids particularly fentanyl and is associated with a marked increase in the number of fatalities associated with drug overdose. While opioid antagonists such as naloxone can rapidly reverse the effects of fentanyl, they do not counteract the sedation, bradycardia and hypotension due to xylazine. There are no highly selective α_2A-AR agonists, and no α_2B or α_2C-AR selective agonists.

Antagonists
There are several high affinity non-selective α₂-AR antagonists (e.g. yohimbine, rauwolscine, RX821002, atipamezole and RS79948), although only atipamezole has found a clinical use for reversing the effects of xylazine and dexmedetomidine in veterinary medicine. This role has yet to be established in human medicine. Of the antagonists, BRL 44408 displays some selectivity for α_2A-AR and MK-912 and JP1302 for the α_2C-AR [126]. Highly selective and potent α_2C-AR antagonists are emerging- ORM-10921 and ORM-12741 - that cross the BBB and have potential utility for treatment of cognitive dysfunction and neuropsychiatric symptoms. There are no α_2B-AR selective antagonists.

β-Adrenoceptors

β-adrenoceptor subtypes
In 1967, Lands and coworkers [86], comparing rank orders of potency of agonists in a manner similar to that of Ahlquist, concluded that there were two subtypes of the β-AR. The β₁-AR, the dominant receptor in heart was equally sensitive to noradrenaline and adrenaline, whereas the β₂-AR, responsible for relaxation of vascular, uterine, and airway smooth muscle, was more sensitive to adrenaline than noradrenaline.
Subsequently it became apparent that not all of the β-AR-mediated responses can be classified as either β₁ or β₂, suggesting the existence of at least one additional subtype [7,23] that was subsequently identified and cloned [50]. The β₃-AR is less sensitive to the commonly used β-AR antagonists and was referred to as the "atypical" β-adrenoceptor. However, not all "atypical β-AR responses" could be explained by the β₃-AR, so for example there was a suggestion of a fourth β-AR, localized in cardiac tissues of various species [77], activated with low potency by noradrenaline and adrenaline, and blocked by β-AR antagonists such as bupranolol and CGP 20712A [61,135]. Although some of the pharmacology overlapped with the β₃-AR, the receptor-mediated responses remained in β₃-AR knockout mice [79-80]. Furthermore, this pharmacology was not seen in β₁-AR knockout mice. CGP 12177 was originally described as an agonist at the putative β₄-AR but is now listed as a partial agonist at the β₁-AR in heart. Thus, CGP 12177 binds as a neutral antagonist inhibiting the catecholamines and many agonists with subnanomolar affinity, but has agonist actions at high concentration (30 nM) making this incompatible with a single site of action. Cellular studies demonstrated that whenever the β₁-AR was present (rat or human), the secondary site of activation was also present [9,13,65,85,117]. Thus the agonist actions of CGP 12177 result from an action at a non-catecholamine site on the β₁-AR [14]. It is now accepted that there are two active sites or conformations of the β₁-AR, a catecholamine conformation where most agonists have their actions and readily blocked by most β-AR antagonists, and a secondary site where CGP 12177 (and several other compounds) are agonists and where responses require considerably higher concentrations of β-AR antagonists for inhibition. This secondary conformation also explains the two-component dose-response curves seen with several compounds (e.g. pindolol, alprenolol) [11,13,153]. The secondary site involves amino acids at the extracellular end of TM4. Although pharmacological responses can be demonstrated from this secondary conformation in many species, including human [78], and is conserved across species [14] its clinical relevance is unknown.
The β₂-AR was cloned from man [35,82] using probes derived from the hamster β₂-AR [45]. However, it proved difficult to clone the β₁-AR using this breakthrough, because the human β₂-AR cDNA did not cross-hybridize with the β₁-AR. The approach that worked utilised the related 5-HT_1A receptor [54], that was isolated using the β₂-AR cDNA as a probe [83] and then used to probe a human placental cDNA library and identify the β₁-AR [59]. The β₃-AR was subsequently cloned [50] using the coding regions of the turkey β₁-AR and the human β₂-AR to screen a human genomic library. Splice variants of the β₃-AR have been reported in mouse [53].

β-adrenoceptor expression
β-AR subtypes are important therapeutic targets and are widely distributed in peripheral organs and tissues and in the CNS. β₁-AR are present in the heart where stimulation increases heart rate (chronotropy), force of contraction (inotropy), rate of conduction through the AV node (dromotropy) and relaxation during diastole (lusitropy) [77] and relaxation of the coronary arteries. In the kidney, β₁-AR stimulation increases renin release from the juxtaglomerular apparatus (JGA) [29]. Other peripheral human tissues with significant populations of β₁-AR include adipose tissue and salivary gland. In brain, β₁-AR are present in the cerebral cortex, hippocampus, amygdala, pineal, putamen and accumbens.
β₂-AR have a wide distribution in the human body including lung, arteries, skeletal muscle, tongue, heart [148], adipose tissue, bone marrow, spleen, gall bladder, brain and adipose tissue. β₂-AR are also present in many immune cells. In the lung, β₂-AR are present in airway smooth muscle where activation results in the important clinical response of bronchodilation. β₂-AR are also present in airway epithelial cells, goblet ells, type II pneumocytes and inflammatory cells (e.g. mast cells and eosinophils). In arteries and veins β₂-AR stimulation causes vasodilatation and in the heart positive inotropic and chronotropic responses. Within the heart, 80% of all β-AR are of the β₁-AR subtype [24], but the 20% β₂-AR in myocardium are more concentrated in the AV node, AV bundle, Purkinje tissue and papillary muscle where they may comprise up to 50-80% of total β-AR present [49,147-148]. In brain, β₂-AR are highly expressed in the substantia nigra and hippocampus with more modest expression in amygdala, thalamus, locus coeruleus and spinal cord. In hippocampus, agonist stimulation of the β₂-AR located on astrocytes promote glucose uptake and glutamate production and stimulation promotes memory consolidation [31,62]. In bone marrow and spleen, β₂-AR are associated with modulation of immune functions and in adipose tissue influence lipolysis. β₂-AR activation also produces increased glucose uptake and anabolic effects in skeletal muscle and glycogenolysis and gluconeogenesis in the liver. High expression of β₂-AR also occurs in reproductive tissues in the male with significant expression in the penis, prostate and epididymis and in the female in breast, vagina, placenta and uterus where functions are more obscure but likely involve relaxation of smooth muscle.
β₃-AR have a localised distribution in humans being present in urinary and gall bladder, with lower expression in fat, intestine and brain [149]. In the urinary bladder β₃-AR activation relaxes the detrusor muscle and increases bladder capacity, whereas in gastrointestinal tissues β₃-AR mediate relaxation [133]. In females, high concentrations of β₃-AR are expressed in the ovary, fallopian tubes, uterine endometrium and placenta [149].
There are considerable differences between rodent and human β₃-AR. Rodent β₃-AR have several splice variants and ligands display markedly different pharmacological characteristics. β₃-AR are highly expressed in rodent white (WAT) and particularly brown (BAT) adipose tissue where they are very important in mediating rodent lipolysis and thermogenesis respectively (the expression and function of β₃-AR in these tissues in humans is less important) [140].

β-adrenoceptor signalling
All three β-AR subtypes couple to G_s-proteins to activate adenylyl cyclase. Stimulation of adenylyl cyclase causes the conversion of ATP into cAMP that activates protein kinase A, that in turn phosphorylates several substrates, for example L-type Ca²⁺ channels. In addition to the PKA pathway cAMP also activates Epac (exchange protein directly activated by cAMP) that modulates cell-type specific protein-protein and protein-lipid interactions that control fine-tuning of important biologic responses [141]. In heart, β₁-AR stimulation increases cardiac output, and in blood vessels β₁-AR mediated vasodilation. In lungs, β₂-AR stimulation of smooth muscle results in bronchodilation and in blood vessels, vasodilatation. In skeletal muscle β₂-AR mediated cAMP signalling cases tremor and is also associated with mTORC2 activation that promotes GLUT4 translocation and increased glucose uptake. In adipocytes β₃-AR activation leads to phosphorylation and activation of the hormone sensitive lipase and perilipins [36]. Other kinases including ERK1/2, p38MAPK and AMP kinases are also activated and PKA may be involved [36].
Prolonged activation of β₂-AR and activation of β₃-AR also promotes coupling to G_i in some systems to produce adenylyl cyclase inhibition that reduces the conversion of ATP to cAMP. βγ subunits from G_i are also likely involved in ERK1/2 phosphorylation following β-AR activation [67]. There is also stimulation of guanylyl cyclase (GC) that causes an increase in cGMP levels, and subsequent activation of protein kinase G.
The human β₂-AR structure was solved by X-ray crystallography: a 3.4 Ä structure of the wild type β₂-adrenoceptor in complex with a conformationally sensitive Fab [82]; and a 2.4 Ä structure of a β₂-AR engineered to facilitate crystal formation [34]. This was the first 7-transmembrane receptor for a hormone or neurotransmitter to have its crystal structure solved, and it provided a relevant template for homology models of closely related monoamine and other 7-transmembrane receptors. Agonist, antagonist and G protein receptor complexes have been solved for β₁- and β₂-AR and a β₃-AR structure has been recently described [1,5,43,72,91,93,96-97,102,109,118,132,139,146,150,155,157,161].

Selectivity and clinical uses of drugs acting at β-adrenoceptors
Agonists
Adrenaline and noradrenaline are used clinically to support blood pressure in cases of shock (septic and cardiogenic). Adrenaline is also used in anaphylaxis and in cardiac arrest. The non-selective β-AR agonist isoprenaline is also used to increase heart rate as a bridge to a permanent pacing system in those with profound bradycardia. (-)-Ro 363 is the only β-AR agonist that displays significant selectivity for the β₁-AR subtype. Noradrenaline and denopamine display a minor degree of selectivity for β₁-AR. Some effort was put into developing somewhat selective β₁-AR partial agonists (ligands with intrinsic sympathomimetic activity ISA) with a view to the treatment of heart failure. However clinical trials with xamoterol revealed an increase in mortality in severe heart failure [38]. Xamoterol, denopamine and dobutamine have varying degrees of β₁-AR selectivity and previously have been used over short periods to maintain cardiac function.
Considerable effort has been put into developing selective β₂-AR agonists, over the last 100 years, that are first line treatments for amelioration of asthma and COPD. Salbutamol and terbutaline are examples of short acting β₂-AR agonists (SABAs), salmeterol and formoterol are long acting agonists (LABAs) and indacaterol, olodaterol and vilanterol are ultra-long acting agonists (ultra-LABAs) [19]. Development of β-agonists for asthma was not always straightforward with certain preparations being linked in epidemics of increased asthma death rates. There are several non- or less selective high efficacy β-agonists not in clinical use e.g., fenoterol and cimaterol. Clenbuterol is included on the World Anti-Doping Authority's list of banned substances due to its popularity as a drug used by bodybuilders to increase skeletal muscle mass and for weight loss [76]. However, there is evidence to show that clenbuterol may have potential for the treatment of type II diabetes [76,136].
The species orthologs of the human β₃-ARs found in the rat, mouse, and cow have significantly different agonist pharmacology that has proved problematic for drug development. For example, BRL 37344 is a potent full agonist at rodent β₃-AR but a weak partial agonist at the human β₃-AR [6] and carazolol has a much higher affinity for the bovine receptor [108], whereas [¹²⁵I]CYP has lower affinity [143]. Carazolol is a potent high efficacy partial agonist at β₃-AR but is also a potent partial agonist at β₁-AR and a highly potent antagonist at β₂-AR [11]. Since the β₃-AR largely lacks sites required for receptor phosphorylation it is less susceptible to desensitisation than the other β-AR subtypes. However, desensitisation can occur associated with mRNA and protein down regulation of receptor and post receptor signalling proteins and there is also evidence for cell specific events [112]. Ligands acting at β₃-AR can also display ligand-directed signalling [137-138]. Vibegron, and mirabegron are selective β₃-AR agonists that potently activate human β₃-AR [73]. The identification of high levels of β₃-AR mRNA in bladder together with a relaxation response to β₃-AR agonists suggested that they could be useful for the treatment of overactive bladder syndrome [99]. Vibegron and mirabegron have been successfully introduced as treatments for this condition [99]. The availability of these human β₃-AR selective compounds has also recreated interest in possible metabolic effects of these compounds [41].
The human β₃-AR appears to exist in at least two agonist conformations [8], in a similar manner to the β₁-AR, due to some residues not conserved in the β₂-AR. There is no evidence for a secondary conformation of the β₂-AR. At the human β₃-AR fenoterol stimulates responses utilising the catecholamine conformation whereas alprenolol, SR58230A and CGP12177 utilise a secondary conformation [8].

Antagonists
propranolol is described as a non-selective β-AR antagonist but is slightly selective for β₂-AR and has very low affinity for β₃-AR. Carvedilol is a non-selective β-AR and α₁-AR antagonist used to treat cardiac failure. It has been suggested to be a β-arrestin biased agonist [160] but this characteristic has been challenged [17] with evidence supporting low efficacy activation of G_s coupled β₂-ARs as the explanation. Other β-antagonists commonly used to reduce arrhythmias, in ischaemic heart disease and in heart failure are bisoprolol, metoprolol and nebivolol. Most so-called cardioselective (β₁-AR selective) β-AR antagonists such as atenolol and metoprolol display only modest selectivity for β₁-AR (bisoprolol is somewhat better) and are associated with side effects due to significant blockade of β₂-AR [10]. CGP 20712A is the most selective β₁-AR antagonist available [10] and is widely used in in vitro studies but is unsuitable for clinical use. NDD-713 and NDD-825 are high-affinity, β₁-AR selective ligands devoid of agonist activity, off-target effects, and toxicology issues, but with good distribution, metabolism and elimination properties [12]. These ligands are largely devoid of β₂-AR-mediated adverse effects and may be beneficial in patients with cardiovascular and respiratory disease or limb ischemia. Some β-blockers have other anti-arrhythmic properties (e.g. sotalol, used for paroxysmal AF). The main action of propafenone (class 1C antiarrhythmic) is to block voltage gated Na⁺ channels (see the Voltage-gated sodium channels family in the Ion Channels section of this website for further details) but is also a weak β-AR antagonist. Labetolol is the β-AR antagonist of choice in pregnancy. Esmolol is a serum esterase sensitive β-AR antagonist and as such only has a short duration of action. It is used in medical emergencies in the operating theatre and in intensive care settings.
ICI 118551 is the most selective β₂-AR antagonist currently available but is only used in in vitro and in animal studies [10]. Some clinically available compounds (e.g. timolol) that are used for ischaemic heart disease and glaucoma are somewhat β₂-AR selective whilst others used for similar conditions (e.g. betaxolol) are marginally β₁-AR selective. There are increasing suggestions that β-AR antagonists (most commonly aimed at β₂-AR) may reduce the growth and spread of some cancers.
A number of antagonists such as nadolol, tertatolol and propranolol can behave in some systems as agonists at the β₃-AR [21-22,145]. Propranolol is primarily a β₁-/β₂-AR antagonist with lower affinity for β₃-AR. SR59230A that is often described as a selective antagonist at β₃-AR displays little selectivity and has similar potency at all 3 subtypes (in fact higher affinity at β₂-AR) [11,100] - what it does have is reasonable potency at blocking β₃-AR. L-748337 is currently the most selective antagonist at the human β₃-AR [11,99,152].

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