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

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

Adrenoceptors in GtoPdb v.2021.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [60, 186]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D 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 [125I]HEAT (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 α1A-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 α2A, α2B and α2C 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 are species variations 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 (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [31] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used 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. 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 (pKi 8.2-9.2) and cyanopindolol (pKi 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 [320] 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) [507]. 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 [189]

Dimer-dependent allosteric modulation within GPCR signalling complexes can influence signalling diversity

G protein-coupled receptors (GPCRs) comprise the largest group of cell surface receptors, translating environmental signals into cellular responses via cognate G protein partners. Contrary to our initial understanding, most GPCRs do not function in living cells as monomers, but most likely dimers, or even larger arrays of receptors. Standard drug design approaches rely on the notion that drugs binding the two receptors in a given dimer likely function independently of one another. However, this view has been challenged by recent work showing that ligand binding at both receptors can modulate dimeric receptors via allosteric communication. While one receptor may actually be needed to drive signalling, the other acts to control or modulate these signals, without a direct signalling outcome itself. Based on the notion of allosteric modulation within homo- and heterodimers, I tested and compared changes in signalling downstream as well as at the level of the receptor-G protein-effector (RGE) complex in response to different combinations of ligands at each protomer. Using a combination of calcium, cyclic adenosine monophosphate, and mitogen-activated protein kinase signalling assays, I have demonstrated functional interactions for a putative D2 dopamine receptor, oxytocin receptor heterodimer (D2R/OTR), in HEK 293 cells. Immunoprecipitation, bioluminescence resonance energy transfer (BRET) and confocal microscopy experiments reveal D2R and OTR do in fact form a heterodimer in vitro, which may explain the nature of these potential allosteric functional interactions. Using BRET, I assessed the RGE complex conformational dynamics in HEK 293 cells for two other heterodimers, β2-adrenergic receptor with cannabinoid CB1 receptor (β2AR/CB1R) and β2AR/OTR, in order to determine how they manifest in parallel to signalling events themselves. These studies reveal functional interactions can occur in terms of signalling complex conformation. Thus GPCR signalling can be modulated by its partner receptor at the level of downstream effector signalling or at the level of the signalling complex itself. With that said, putative heterodimers need to be reanalyzed in vivo for their allosteric properties, which may explain some of the side effects of so many drugs, and may have implications in drug design.Les récepteurs couplés aux protéines G (RCPG) constituent le plus grand groupe de récepteurs de la surface cellulaire, qui traduisent les signaux environnementaux en réponses cellulaires via leurs protéines G associées. Contrairement à notre compréhension initiale, la majorité des RCPG ne fonctionnent pas en tant que monomères, mais possiblement en tant que dimères ou même oligomères. Les approches actuelles de conception de médicament estiment que lors de la liaison d'un médicament aux deux récepteurs d'un dimère quelconque, ces derniers fonctionnent potentiellement indépendamment l'un de l'autre. Cependant, cette notion a été reconsidérée par une étude récente montrant que la liaison d'un ligand aux deux récepteurs peut les altérer par voie de communication allostérique. Alors qu'un premier récepteur peut être requis pour initialiser la signalisation, un second peut contrôler ou modifier ces signaux, n'ayant pas nécessairement une signalisation directe comme résultante. Dans l'étude suivante, basée sur la notion de modulation allostérique au sein d'homodimère et d'hétérodimère, les changements de signalisation en aval ainsi qu'au niveau du complexe récepteur/protéine G/effecteur (RGE) ont été étudiés et comparés en réponse à différentes combinaisons de ligands pour chaque protomère. En utilisant une combinaison d'essais de signalisation de calcium, d'adénosine monophosphate cyclique (cAMP) et de protéine kinase activée par des agents mitogènes (MAPK), une interaction fonctionnelle entre le récepteur dopaminergique D2 et le récepteur de l'ocytocine (D2R/OTR) a été démontrée dans les cellules HEK 293. Des expériences d'immunoprécipitation, de transfert d'énergie de résonance par bioluminescence (BRET) et de microscopie confocale ont révélé la présence d'hétérodimère entre le D2R et l'OTR in vitro, ce qui pourrait expliquer la nature des interactions fonctionnelles allostériques. En utilisant la technique de BRET, la dynamique fonctionnelle du complexe RGE dans les cellules HEK 293 a été examinée chez deux autres hétérodimères, soit celui composé du récepteur adrénergique β2 et du récepteur cannabinoïde CB1 (β2AR/CB1R) et l'hétérodimère β2AR/OTR, afin de déterminer comment ils traduisent les évènements de signalisation. Ces études démontrent donc qu'une interaction fonctionnelle peut survenir sur le plan de la conformation du complexe de signalisation. Par conséquent, la signalisation d'un RCPG peut être modulée par son récepteur partenaire au niveau des effecteurs ou au niveau du complexe de signalisation lui-même. Pour cette raison, il serait impératif de réanalyser in vivo les propriétés allostériques d'hétérodimères putatifs, ce qui pourrait expliquer certains effets secondaires d'une multitude de médicaments et ce qui pourrait impliquer des changements majeurs dans la façon de concevoir de nouveaux médicaments