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The signaling and selectivity of ?-adrenoceptor agonists for the human ?2A, ?2B and ?2C-adrenoceptors and comparison with human ?1 and ?-adrenoceptors

Proudman, Richard G. W.; Akinaga, Juliana; Baker, Jillian G.


Richard G. W. Proudman

Juliana Akinaga

Professor of Drug Discovery and Respiratory Medicine


?2-adrenoceptors, (?2A, ?2B and ?2C-subtypes), are Gi-coupled receptors. Central activation of brain ?2A and ?2C-adrenoceptors is the main site for ?2-agonist mediated clinical responses in hypertension, ADHD, muscle spasm and ITU management of sedation, reduction in opiate requirements, nausea and delirium. However, despite having the same Gi-potency in functional assays, some ?2-agonists also stimulate Gs-responses whilst others do not. This was investigated. Agonist responses to 49 different ?-agonists were studied (CRE-gene transcription, cAMP, ERK1/2-phosphorylation and binding affinity) in CHO cells stably expressing the human ?2A, ?2B or ?2C-adrenoceptor, enabling ligand intrinsic efficacy to be determined (binding KD /Gi-IC50 ). Ligands with high intrinsic efficacy (e.g., brimonidine and moxonidine at ?2A) stimulated biphasic (Gi-Gs) concentration responses, however for ligands with low intrinsic efficacy (e.g., naphazoline), responses were monophasic (Gi-only). ERK1/2-phosphorylation responses appeared to be Gi-mediated. For Gs-mediated responses to be observed, both a system with high receptor reserve and high agonist intrinsic efficacy were required. From the Gi-mediated efficacy ratio, the degree of Gs-coupling could be predicted. The clinical relevance and precise receptor conformational changes that occur, given the structural diversity of compounds with high intrinsic efficacy, remains to be determined. Comparison with ?1 and ?1/?2-adrenoceptors demonstrated subclass affinity selectivity for some compounds (e.g., ?2:dexmedetomidine, ?1:A61603) whilst e.g., oxymetazoline had high affinity for both ?2A and ?1A-subtypes, compared to all others. Some compounds had subclass selectivity due to selective intrinsic efficacy (e.g., ?2:brimonidine, ?1:methoxamine/etilefrine). A detailed knowledge of these agonist characteristics is vital for improving computer-based deep-learning and drug design.


Proudman, R. G. W., Akinaga, J., & Baker, J. G. (2022). The signaling and selectivity of ?-adrenoceptor agonists for the human ?2A, ?2B and ?2C-adrenoceptors and comparison with human ?1 and ?-adrenoceptors. Pharmacology Research and Perspectives, 10(5), Article e01003.

Journal Article Type Article
Acceptance Date Aug 15, 2022
Online Publication Date Sep 13, 2022
Publication Date Oct 1, 2022
Deposit Date Sep 14, 2022
Publicly Available Date Sep 14, 2022
Journal Pharmacology research & perspectives
Electronic ISSN 2052-1707
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 10
Issue 5
Article Number e01003
Keywords General Pharmacology, Toxicology and Pharmaceutics; Neurology
Public URL
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