Adrenoceptors in GtoPdb v.2024.2

Abstract

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [116, 324].

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 [64] 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 [520] 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) [819]. 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 [327].