The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [22,55].

Adrenoceptors, α₁
The three α₁-adrenoceptor subtypes α_1A, α_1B and α_1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α₁- relative to α₂-adrenoceptors. [³H]Prazosin and HEAT (BE2254) (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca²⁺ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α₁-adrenoceptors. α₁-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1_A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α₁- and β₂-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α₁-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α₁-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension.

Adrenoceptors, α₂
The three α₂-adrenoceptor subtypes α_2A, α_2B and α_2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. Brimonidine (UK14304) and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α₂- relative to α₁-adrenoceptors. [³H]Rauwolscine, [³H]brimonidine (UK14304) and [³H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α_2A-adrenoceptor. Multiple mutations of α₂-adrenoceptors have been described, some associated with alterations in function. Presynaptic α₂-adrenoceptors regulate many functions in the nervous system. The α₂-adrenoceptor agonists clonidine, guanabenz and brimonidine (UK14304) affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. Clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. Dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [14] and veterinary medicine and has sympatholytic and anxiolytic properties. The α₂-adrenoceptor antagonist mirtazapine is used as an anti-depressant. 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. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools.

Adrenoceptors, β
The three β-adrenoceptor subtypes β₁, β₂ and β₃ are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α₁- and α₂-adrenoceptors, while propranolol (pK_i 8.2-9.2) and cyanopindolol (pK_i 10.0-11.0) are relatively selective antagonists for β₁- and β₂- relative to β₃-adrenoceptors. (-)-Noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β₁- relative to β₂-adrenoceptors. Pharmacological differences exist between human and mouse β₃-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β₃-adrenoceptors [88]. β₃-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β₃-adrenoceptors, but does not discriminate between the three β- subtypes [84] whereas L-748337 is more selective. [¹²⁵I]-cyanopindolol, [¹²⁵I]-hydroxy benzylpindolol and [³H]-alprenolol are high affinity radioligands that label β₁- and β₂- adrenoceptors and β₃-adrenoceptors can be labelled with higher concentrations (nM) of [¹²⁵I]-cyanopindolol together with β₁- and β₂-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β₁-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β₁-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [146]. Cardiac failure is also treated with carvedilol that blocks β₁- and β₂-adrenoceptors, as well as α₁-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β₂-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β₁- and β₂-adrenoceptors and there are no β₂-adrenoceptor-selective antagonists used therapeutically. The β₃-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [56].

Adrenoceptors, α₁
The three α1-adrenoceptor subtypes are α_1A, α_1B and α_1D. The previously described α_1C-adrenoceptor is a species homologue that corresponds to the pharmacologically defined α_1A-adrenoceptor [55]. Some tissues possess α_1A-adrenoceptors (termed α_1L-adrenoceptors [46,89]) 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 [108]. 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-α_1B- or β₂--β₂-adrenoceptors [50,134]. In blood vessels all three α_1--adrenoceptor subtypes are located both at the cell surface and intracellularly [79-80]. Signalling is predominantly via G_q/11 but α₁-adrenoceptors also couple to G_i/o, G_s and G_12/13. Several α_1A-adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [40] although some bias appears to relate to off-target activity [28] . 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 [44].

Adrenoceptors, α₂
The three α₂-adrenoceptor subtypes are termed α_2A, α_2B and α_2C. ARC-239 and prazosin show some selectivity for α_2B- and α_2C-adrenoceptors over α_2A-adrenoceptors. Oxymetazoline is an imidazoline partial agonist that also binds to non-GPCR binding sites for imidazolines, classified as I₁, I₂ and I₃ [30] at which catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands with hypotensive effects in vivo. I₁-imidazoline recognition sites cause central inhibition of sympathetic tone, I₂-imidazoline sites are an allosteric binding site on monoamine oxidase B, and I₃-imidazoline sites regulate insulin secretion from pancreatic β-cells. α_2A-adrenoceptor stimulation reduces insulin secretion from β-islets [148], 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 [112]. The α_2A- and α_2C-adrenoceptors form homodimers [122]. 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 [122,131,138]. Signalling by α₂-adrenoceptors is primarily via G_i/o, although the α_2A-adrenoceptor also couples to G_s [38]. Imidazoline compounds display bias relative to each other at the α_2A-adrenoceptor [97]. The noradrenaline reuptake inhibitor desipramine acts directly on α_2A-adrenoceptors to promote internalisation via recruitment of β-arrestin [27]. The structure of the α_2B-adrenoceptor has recently been determined by cryo-EM in complex with dexmedetomidine and Gα_o at a resolution of 2.9 Å providing insights into the structural requirements required for interactions with α₂-adrenoceptor agonists [151].

Adrenoceptors, β
The three β-adrenoceptors are termed β₁, β₂ and β₃. [¹²⁵I]ICYP can be used to define either β₁- or β₂-adrenoceptors when conducted in the presence of a β₁- or a β₂-adrenoceptor-selective antagonist. A fluorescent analogue of CGP 12177 is used to study β-adrenoceptors in living cells [12]. [¹²⁵I]ICYP at higher (nM) concentrations has been used to label β₃-adrenoceptors in systems with few if any other β-adrenoceptor subtypes. The β₃-adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [41], where the isoforms display different signalling characteristics [59]. There are three β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) with pharmacology that differs from the human β-adrenoceptors [6]. Numerous polymorphisms have been described for the β-adrenoceptors; some are associated with altered signalling and trafficking, susceptibility to disease and/or altered responses to pharmacotherapy [70]. All β-adrenoceptors couple to G_s (activating adenylyl cyclase and elevating cAMP levels), but the β₂- and β₃-adrenoceptors in particular can also activate G_i and the β₂-adrenoceptor activates β-arrestin-mediated signalling. Many β₁- and β₂-adrenoceptor antagonists are agonists at β₃-adrenoceptors (CL316243, CGP 12177 and carazolol). Many ‘antagonists’ of cAMP accumulation, for example carvedilol and bucindolol, weakly activate MAP kinase pathways [10,42,48-49,114-115] and thus display biased agonism. Bupranolol acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β₂-adrenoceptor via G_s or arrestins [37]. X-ray crystal structures have been described of the agonist bound [139] and antagonist bound forms of the β₁- [140], agonist-bound [26] and antagonist-bound forms of the β₂-adrenoceptor [109,111], as well as a fully active agonist-bound, G_s protein-coupled β₂-adrenoceptor [110], as well as providing insights into the structural requirements for agonist, partial agonist, antagonist, G protein and β-arrestin coupling [143]. Structures have also been described for negative allosteric modulators of the β₂-adrenoceptor [73]. Cryo-EM studies have also been recently described that provide a structural framework for agonist mediated signal transduction [127]. The agonists carvedilol and bucindolol bind to a site on the β₁-adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [140]. Compounds displaying β-arrestin-biased signalling at the β₂-adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for G_s coupling promote movement of TM5 and TM6 [72]. 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 [66,77,93]. Such flexibility likely has consequences for our understanding of allosterism and biased agonism, and for the future therapeutic exploitation of these phenomena.

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Subcommittee members: Roger J Summers 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

Other contributors: Jillian G. Baker Cell Signalling School of Life Sciences C Floor Medical School Queen's Medical Centre University of Nottingham Nottingham UK