The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [25,56].

Adrenoceptors, α₁
There are three α₁-adrenoceptor subtypes α_1A, α_1B and α_1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Signalling is predominantly via G_q/11 but α₁-adrenoceptors can also couple to G_i/o, G_s and G_12/13 [80]. Adrenoceptors are primarily located in blood vessels and in the brain, with the α_1A subtype also present in the urogenital tract.
Clinical uses: α₁-Adrenoceptor antagonists are used to treat hypertension (doxazosin, terazosin [69]), hypertension in pregnancy (labetalol), benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin [53]), PTSD (doxazosin, prazosin) and phaeo-chromocytoma (phenoxybenzamine, phentolamine).
α_1A-Adrenoceptor agonists are used short-term as nasal decongestants (xylometazoline and oxymetazoline), although they also activate imidazoline and α_2A-receptors. Adrenaline and noradrenaline can be given by infusion to treat hypotension in shock.
Antagonists: High affinity, non-selective α₁-adrenoceptor antagonists include (+)-cyclazosin, doxazosin, prazosin and terazosin. Fluorescent derivatives of prazosin (BODIPY FL-prazosin) are used to examine cellular localisation of α₁-adrenoceptors. [³H]Prazosin and [¹²⁵I]HEAT (BE2254) are α₁-selective antagonist radioligands. α_1A-Subtype selective antagonists include SNAP5089, silodosin, RS-100329 and S(+)-niguldipine (although this also has high affinity for L-type Ca²⁺ channels). Several anti-depressants and anti-psychotic drugs also have high α_1A-adrenoceptor antagonist affinity that may contribute to their CNS actions but likely also contribute to side effects such as orthostatic hypotension [52]. BMY-7378 has α_1D-subtype selectivity.
Agonists: High efficacy non-selective α₁-adrenoceptor agonists include phenylephrine, methoxamine, etilefrine, naphazoline and cirazoline (relative to α₂- and β-adrenoceptors). A61603 is selective for the α_1A-subtype.
Species differences: Few species differences have been reported for α₁-adrenoceptor ligands.

Adrenoceptors, α₂
There are three α₂-adrenoceptor subtypes α_2A, α_2B and α_2C that are activated by the endogenous agonists (-)-adrenaline and with lower potency by (-)-noradrenaline. α₂-Adrenoceptor signalling is predominantly via G_i/o but they can also couple to G_s. α₂-Adrenoceptors cause inhibition of voltage dependent Ca²⁺ channels and augment inwardly rectifying K⁺ channels [39,80]. All α₂-adrenoceptor subtypes may be located pre- or post-junctionally and are primarily located in brain and kidney with α_2A- and α_2C- subtypes present in blood vessels and α_2A- in spleen and pancreas.
Clinical uses: α₂-Adrenoceptor antagonists are not used clinically. α₂-Adrenoceptor agonists are used to treat hypertension (clonidine, moxonidine, acting via central baroreflex control), to induce analgesia, sedation and anxiolysis (dexmedetomidine), for ADHD (guanfacine), in glaucoma and rosacea (brimonidine (UK14304)) and muscle spasm (tizanidine), as short-term nasal decongestants (xylometazoline and oxymetazoline that also activate imidazoline [21] and α_1Areceptors), and increasingly to treat opioid withdrawal.
Antagonists: High affinity, non-subtype selective α₂-adrenoceptor antagonists include rauwolscine, yohimbine, RX821002, atipamezole and RS79948 [16]. [³H]Rauwolscine and [³H]RX821002 are α₂-selective antagonist radioligands. BRL 44408 has some α_2A-selectivity and MK-912 and JP1302 some α_2C-selectivity. Idazoxan, an early α₂-adrenoceptor antagonist, also has significant binding to imidazoline receptors [21] (and 5-HT receptors).
Agonists: brimonidine (UK14304) is a high efficacy non-subtype selective α₂-adrenoceptor agonist (relative to α₁- and β-adrenoceptors). Other agonists include talipexole, apraclonidine (para-amino-clonidine), clonidine, guanfacine, medetomidine and dexmedetomidine. [³H]Brimonidine (UK14304) is an α₂-selective agonist radioligand. Oxymetazoline has significant α₂-adrenoceptor agonism, but it is also an α_1A and imidazoline receptor agonist [21].
Species differences:There are species variations in the pharmacology of the α_2A-adrenoceptor with regard to antagonists although agonist pharmacology is very similar.

Adrenoceptors, β
There are three β-adrenoceptor subtypes β₁, β₂ and β₃ that are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Signalling is predominantly via G_s, although there are reports of G_i-coupling and ERK1/2 phosphorylation, and the β₂-adrenoceptor also activates β-arrestin-mediated signalling [80]. β₁-Adrenoceptors are primarily present in heart, blood vessels, kidney and brain; β₂-adrenoceptors in lungs, blood vessels, skeletal muscle, heart and brain; and β₃-adrenoceptors in the human bladder but also have an important role in rodent brown and white fat.
Clinical uses: β-Adrenoceptor antagonists are widely used to treat heart failure, arrhythmias, ischaemic heart disease and hypertension (bisoprolol, carvedilol, metoprolol, nebivolol) [151-152]. Labetalol is used in pregnancy to treat hypertension. β-Adrenoceptor antagonists are also used to treat glaucoma (betaxolol, timolol), anxiety, migraine, benign essential tremor, thyrotoxicosis, portal hypertension and variceal bleeding (propranolol for all). Propranolol is the first line treatment for infantile haemangioma, and there is increasing interest in β-adrenoceptor antagonist use to reduce primary growth and metastasis in cancer [57]. Non-selective β-adrenoceptor agonists are used to treat cardiac arrest and anaphylaxis ((±)-adrenaline), via infusion for shock ((±)-adrenaline and noradrenaline), and as a bridge to pacemaker implantation in bradycardia (isoprenaline). Selective β₂-adrenoceptor agonists are used to relieve asthma and COPD (short-acting salbutamol, terbutaline; long-acting salmeterol and formoterol, and ultra-long acting indacaterol, olodaterol and vilanterol) [15]. β₃-Adrenoceptor agonists are used to treat overactive bladder syndrome (mirabegron, solabegron and vibegron) [53].
Antagonists: High affinity, non-selective β-adrenoceptor antagonists include propranolol, carvedilol, timolol and bupranolol, although for human receptors, all compounds appear to have lower affinity for human β₃-adrenoceptors than for β₁- or β₂-adrenoceptors. Fluorescent analogues of β-ligands e.g. CGP 12177 and propranolol can be used to label β-adrenoceptors at the cellular level [13]. [¹²⁵I]ICYP, [³H]CGP12177 and [³H]dihydroalprenolol are high affinity radioligands that label β₁- and β₂-adrenoceptors and at higher concentrations, β₃-adrenoceptors. CGP 20712A and NDD-825 are highly β₁-selective antagonists and ICI 118551 is a β₂-selective antagonist [16].
Agonists: isoprenaline and cimaterol are highly efficacious non-selective β-adrenoceptor agonists (relative to α₁- and α₂-adrenoceptors). Formoterol, salmeterol and vilanterol have high β₂-adrenoceptor selectivity whilst mirabegron, solabegron and vibegron have β₃-adrenoceptor selectivity. L 755507 and L-748337 are partial agonists that display human β₃-adrenoceptor selectivity. [³H]L748337 can be used to selectively label β₃-adrenoceptors in human and rat tissues [143].
Species differences: rodent β₁ and β₂-adrenoceptors display similar pharmacology to human receptors. There are three β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) with pharmacology that differs from the human β-adrenoceptors [7]. Significant pharmacological differences exist between human and mouse β₃-adrenoceptors, which includes mouse splice variants [43] where the isoforms display different signalling characteristics [60].

Adrenoceptors, &alpha₁
The previously described α_1C-adrenoceptor is a species homologue that corresponds to the pharmacologically defined α_1A-adrenoceptor [56]. Some tissues possess α_1A-adrenoceptors (termed α_1L-adrenoceptors [47,92]) that display relatively low affinity in functional and binding assays for prazosin indicative of different receptor states or locations. α_1A-Adrenoceptor C-terminal splice variants form homo- and heterodimers, and do not generate a functional α_1L-adrenoceptor [112]. Recombinant α_1D-adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is encouraged by truncation of the N-terminus, or by co-expression and formation of heterodimers of with α_1B- or β₂-adrenoceptors [50,140]. α_1B- and α_1D-adrenoceptors form heterodimers with >20 chemokine receptors to regulate leukocyte trafficking [41]. Structural basis for α_1A-adrenoceptor agonist specificity has been determined [130]. In blood vessels all three α₁-adrenoceptor subtypes are located both at the cell surface and intracellularly [82-83]. There are also differences between subtypes in coupling efficiency to different pathways. In vascular smooth muscle, the potency of agonists is related to the predominant subtype, α_1D- conveying greater agonist sensitivity compared to α_1A-adrenoceptors [45]. The β-adrenoceptor antagonists carvedilol and labetalol have some α_1A-adrenoceptor antagonist activity although the contribution of α₁-adrenoceptor blockade to their therapeutic effect is uncertain. Although used for their α-adrenoceptor agonist actions, oxymetazoline and xylometazoline also activate imidazoline receptors which are non-adrenergic receptors. Phenoxybenzamine is considered an irreversible antagonist as it covalently binds to a TM3 cysteine.

Adrenoceptors, α₂
Multiple mutations of α₂-adrenoceptors have been described, with some associated with alterations in function [1]. Presynaptic α₂-adrenoceptors regulate many functions in the nervous system. The structure of the α_2B-adrenoceptor has been determined by cryo-EM in complex with dexmedetomidine and G_αo at a resolution of 2.9Å, providing insights into the structural requirements required for interactions with α₂-adrenoceptor agonists [157]. ARC-239 shows some selectivity for α_2B- and α_2C-adrenoceptors over α_2A-adrenoceptors. Although used for their α-adrenoceptor agonist actions, oxymetazoline and xylometazoline also activate imidazoline receptors which are non-adrenergic receptors [21]. Early α₂-adrenoceptor antagonists such as idazoxan also bind to imidazoline binding sites, whereas later ligands such as RX821002 do not. The anti-depressant mirtazapine has some α₂-adrenoceptor antagonist activity that may contribute to its action [52,106]. The α_2B subtype appears to be involved in neurotransmission in the spinal cord and α_2C in regulating catecholamine release from adrenal chromaffin cells. Adrenoceptor stimulation reduces insulin secretion from pancreatic β-islets [154], with a polymorphism in the 5’-UTR of the ADRA2A gene being associated with increased receptor expression in β-islets and heightened susceptibility to diabetes [116]. α₂-Adrenoceptor agonists also display anti-tumour activity [158]. The α_2A- and α_2C-adrenoceptors form homodimers [124]. Heterodimers between α_2A- and either the α_2C-adrenoceptor or μ-opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [124,136,144].

Adrenoceptors, β
X-ray crystal structures have been described of the agonist bound [145] and antagonist bound forms of the β₁-adrenoceptor [146], agonist-bound [29] and antagonist-bound forms of the β₂-adrenoceptor [113,115], as well as a fully active agonist-bound, G_s protein-coupled β₂-adrenoceptor [114], and these provide insights into the structural requirements for agonist, partial agonist, antagonist, G protein and β-arrestin coupling [148]. Structures have also been described for negative allosteric modulators of the β₂-adrenoceptor [74]. Cryo-EM studies have also been recently described that provide a structural framework for agonist mediated signal transduction [30,131]. The cryo-EM structures of the β₃-adrenoceptor (dog) bound to mirabegron, solabegron or isoprenaline have been described [96,98].
Many ligands originally termed β-antagonists (β-blockers) have partial agonist actions. Clinically this was termed intrinsic sympathomimetic activity (ISA). A high degree of partial agonism appears to correlate with less beneficial effects in heart failure and ischaemic heart disease. Ligands with substantial partial agonism include xamoterol, bucindolol, cyanopindolol, pindolol, carpindolol, alprenolol, oxprenolol, acebutolol, carteolol, ICI-89406 and carazolol. Autoantibodies to β₁-adrenoceptors are associated with heart failure although their role has yet to be fully elucidated [79,137]. The β₁-adrenoceptor (and human β₃-adrenoceptor) exist in at least 2 active conformations whereby many antagonists bind to the orthosteric catecholamine site with high affinity yet stimulate agonist actions utilising a lower affinity secondary conformation. CGP 12177 is the best described, but several ligands have been shown to activate this secondary β₁-adrenoceptor conformation (originally termed “non-conventional agonists”, e.g. CGP 12177, pindolol, alprenolol, carazolol, cyanopindolol).
Several ligands have been described that appear to cause biased signalling via the β₂-adrenoceptor. Whilst this appears consistent for some ligands (e.g. propranolol) it is more controversial for others (e.g. carvedilol) and may be tissue specific. New generation GRK-biased β₂-adrenoceptor partial agonists have potential for the treatment of diabetes and obesity [93]. Compounds displaying β-arrestin-biased signalling at the β₂-adrenoceptor may have a greater effect on the conformation of TM7, whereas full agonists for G_s coupling promote movement of TM5 and TM6 [73]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in the β₂-adrenoceptor that is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstream signalling partners [67,78,99]. Such flexibility likely has consequences for our understanding of allosterism and biased agonism, and for the future therapeutic exploitation of these phenomena.
The ’rodent β₃-adrenoceptor selective’ agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor [90]. SR59230A has been often described as β₃-adrenoceptor selective and does display reasonably high affinity at β₃-adrenoceptors, but does not discriminate between human β₁, β₂ and β₃-subtypes [87].
Numerous polymorphisms have been described for the β-adrenoceptors although none are reliably associated with any change in disease state or response to treatment [2].

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Subcommittee members: Roger J. Summers (Past chairperson) Drug Discovery Biology Monash Institute of Pharmaceutical Sciences Monash University 399 Royal Parade Parkville,Victoria 3052 Australia Martin C. Michel Department of Pharmacology Johannes Gutenberg University Mainz, Germany Jillian G. Baker Cell Signalling School of Life Sciences C Floor Medical School Queen's Medical Centre University of Nottingham Nottingham UK