Adrenoceptors

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

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Adrenoceptors, α1

α1-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; [15]) are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline with equal potency. phenylephrine, methoxamine and cirazoline are agonists selective for α1-adrenoceptors relative to α2-adrenoceptors, while prazosin (8.5–10.5) and corynanthine (6.5–7.5) are antagonists considered selective for α1-adrenoceptors relative to α2-adrenoceptors. [3H]prazosin (0.25 nM) and [125I]HEAT (0.1 nM; also known as BE2254) are relatively selective radioligands. The α1A-adrenoceptor antagonist (+)-niguldipine also has high affinity for L-type Ca2+ channels. The conotoxin ρ-TIA acts as a negative allosteric modulator at the α1B-adrenoceptor [84], while the snake toxin ρ-Da1a acts as a selective competitive antagonist at the α1A-adrenoceptor [74]. Fluorescent derivatives of prazosin (Bodipy PL-prazosin – QAPB) are increasingly used to examine cellular localisation of α1-adrenoceptors. The vasoconstrictor effects of selective α1-adrenoceptor agonists have led to their use as nasal decongestants; antagonists are used to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The combined α1- and β2-adrenoceptor antagonist carvedilol is widely 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 possess α1-adrenoceptor blocking properties that are believed to contribute to side effects such as orthostatic hypotension and extrapyramidal effects.

Adrenoceptors, α2

α2-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; [15]) are activated by endogenous agonists with a relative potency of (-)-adrenaline > (-)-noradrenaline. UK14304 (brimonidine) and BHT920 are agonists selective for α2-adrenoceptors relative to α1-adrenoceptors, rauwolscine (9.0) and yohimbine (9.0) are antagonists selective for α2-adrenoceptors relative to α1-adrenoceptors. [3H]rauwolscine (1 nM), [3H]brimonidine (5 nM) and [3H]RX821002 (0.5 nM and 0.1 nM at α2C) are relatively selective radioligands. There is species variation in the pharmacology of the α2A-adrenoceptor; for example, yohimbine, rauwolscine and oxymetazoline have an ~20-fold lower affinity for rat, mouse and bovine α2A-adrenoceptors compared to the human receptor. These α2A orthologues are sometimes referred to as α2D-adrenoceptors. Multiple mutations of α2-adrenoceptors have been described, some of which are associated with alterations in function. Presynaptic α2-adrenoceptors are widespread in the nervous system and regulate many functions, hence the multiplicity of actions. The effects of classical (not subtype selective) α2-adrenoceptor agonists such as clonidine, guanabenz and UK14304 (brimonidine) on central baroreflex control (hypotension and bradycardia), hypnotic, analgesic, seizure modulation and platelet aggregation are mediated by α2A-adrenoceptors. clonidine has been used as an anti-hypertensive and also to counteract opioid withdrawal. Actions on imidazoline receptors may contribute to the pharmacological effects of clonidine. α2-Adrenoceptor agonists such as dexmedetomidine have been widely used as sedatives and analgesics in veterinary medicine (also xylazine) and are now used frequently in humans. α2-Adrenoceptor antagonists are relatively little used therapeutically although yohimbine has been used to treat erectile dysfunction and several anti-depressants (cyanopindolol, mirtazepine) that block α2-adrenoceptors may work through this mechanism. The roles of α2B and α2C-adrenoceptors are less clear but the α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.

Adrenoceptors, β

β-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors, [15]) are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. isoprenaline is a synthetic agonist 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 selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 are agonists that 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 [81]. β3-Adrenoceptors are relatively resistant to blockade by propranolol (pKi 5.8–7.0), but can be blocked by high concentrations of bupranolol (pKi 8.65,[82]). SR59230A has reasonably high affinity at β3-adrenoceptors [57], but does not discriminate well between the three β-adrenoceptor subtypes [16] and has been reported to have lower affinity for the β3-adrenoceptor in some circumstances [48]. [125I]-cyanopindolol, [125I]-hydroxybenzylpindolol and [3H]-alprenolol are high affinity radioligands widely used to label β1- and β2-adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol in the presence of appropriate concentrations of β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 are also increasingly being used to track β-adrenoceptors at the cellular level [9]. Somewhat selective β1-adrenoceptor selective agonists (denopamine, dobutamine) are used short-term to treat cardiogenic shock but, in the longer term, 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 succesfully treated with carvedilol which blocks both β1- and β2-adrenoceptors, as well as α1-adrenoceptors. β2-Adrenoceptor-selective agonists are powerful bronchodilators widely used to treat respiratory disorders. There are both short (salbutamol, terbutaline) and long acting drugs (formoterol, salmeterol). Although many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors there are no β2-adrenoceptor-selective antagonists used therapeutically. Although potentially useful for the treatment of obesity, there are no β3-adrenoceptor-selective agonists used for this purpose currently. Several β3-adrenoceptor agonists (mirabegron, amibegron and solabegron) are used to control overactive bladder syndrome.

Receptors

α1A-adrenoceptor Show summary » More detailed page

α1B-adrenoceptor Show summary » More detailed page

α1D-adrenoceptor Show summary » More detailed page

α2A-adrenoceptor Show summary » More detailed page

α2B-adrenoceptor Show summary » More detailed page

α2C-adrenoceptor Show summary » More detailed page

β1-adrenoceptor Show summary » More detailed page

β2-adrenoceptor Show summary » More detailed page

β3-adrenoceptor Show summary » More detailed page

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NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation:

Adrenoceptors. Accessed on 23/10/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=4.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA and Harmar AJ, CGTP Collaborators. (2013) The Concise Guide to PHARMACOLOGY 2013/14: G Protein-Coupled Receptors. Br J Pharmacol. 170: 1459–1581.