Adrenoceptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Abstract

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [58], see also [180]. Adrenoceptors, α1α1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. Selective α1-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). 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 and extrapyramidal effects.Adrenoceptors, α2 α2-Adrenoceptors are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of the α2A-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 affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.Adrenoceptors, ββ-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively β1 and β2 adrenoceptor-selective antagonists. (-)-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 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 well between the three β- subtypes whereas L 755507 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. [3H]-L-748337 is a β3-selective radioligand [474]. 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 hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). 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.

β-Adrenoceptor Activation in Breast MCF-10A Cells Induces a Pattern of Catecholamine Production Similar to that of Tumorigenic MCF-7 Cells

“…Interestingly, in MCF-10A cells, activation of β-adrenoceptor caused an increase of the adrenaline/noradrenaline ratio to a profile similar to that observed in the tumorigenic MCF-7 cells. β 2 - and α 2C -adrenoceptors are among the adrenoceptors more often referred to be involved in tumorigenesis and affinity of adrenaline for these receptor subtypes is higher than that of noradrenaline [ 17 ] which suggests that adrenaline may be more efficient in activating pathways involved in tumorigenesis.…”

“…This hypothesis is in line with the established model of drug interaction with G-protein coupled receptors [ 55 ] and, at present, seems to be the most likely to explain why agonists and antagonists of the same receptor type are causing the same response in the same cell model. This hypothesis must be challenged in future studies as it may also contribute to explain the controversy around the role of adrenoceptors in the proliferation of cancer breast cell lines [ 26 , 52 ], and to understand why adrenoceptor agonists could exert their effects in concentrations that are three to four orders of magnitude lower [ 56 ] than the commonly accepted EC 50 values [ 17 ].…”

“…Adrenaline and noradrenaline effects are mediated by a family of G-protein coupled receptors, named adrenoceptors [ 17 ]. Adrenoceptors are subdivided into three major types (α 1 , α 2 , and β), each further divided into three subtypes (α 1A , α 1B , α 1D ; α 2A , α 2B , α 2C ; and β 1 , β 2 , and β 3 ).…”

A photoswitchable ligand targeting β1-adrenoceptor enables light-control of the cardiac rhythm

“…Beta-adrenoceptors (β-AR) are class A G protein-coupled receptors (GPCRs) endogenously activated by the catecholamines adrenaline or noradrenaline, which regulate a variety of biological functions. [1–3] Their crucial role in the regulation of cardiac function and the respiratory system, among others, has signaled them as classical pharmacological targets. [4] β-AR are divided in three subtypes, β 1 -, β 2 - and β 3 -AR.…”

“…All β-AR mainly induce the production of cAMP from ATP through Gs coupling. [1,3] However, their biological effects are noticeably different, majorly due to their different localization in the body. β 1 -adrenoceptors, which regulate the cardiac output, are mainly located in the heart and cerebral cortex.…”