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, α₁
α₁-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 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 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 α_2B subtype appears to be involved in neurotransmission in the spinal cord and α_2C in regulating catecholamine release from adrenal chromaffin cells.

Adrenoceptors, β
β-Adrenoceptors 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 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.