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.

Abstract

?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.

Citation

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. https://doi.org/10.1002/prp2.1003

• 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
• DOI: https://doi.org/10.1002/prp2.1003
• Keywords: General Pharmacology, Toxicology and Pharmaceutics; Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/11195173
• Publisher URL: https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.1003