The affinity and selectivity of α-adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors

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

Abstract

α2-Adrenoceptors, subdivided into α2A, α2B, and α2C subtypes and expressed in heart, blood vessels, kidney, platelets and brain, are important for blood pressure, sedation, analgesia, and platelet aggregation. Brain α2C-adrenoceptor blockade has also been suggested to be beneficial for antipsychotic action. However, comparing α2-adrenoceptor subtype affinity is difficult due to significant species and methodology differences in published studies. Here, 3H-rauwolscine whole cell binding was used to determine the affinity and selectivity of 99 α-antagonists (including antidepressants and antipsychotics) in CHO cells expressing human α2A, α2B, or α2C-adrenoceptors, using an identical method to β and α1-adrenoceptor measurements, thus allowing direct human receptor comparisons. Yohimbine, RX821002, RS79948, and atipamezole are high affinity non-selective α2-antagonists. BRL44408 was the most α2A-selective antagonist, although its α1A-affinity (81nM) is only 9-fold greater than its α2C-affinity. MK-912 is the highest-affinity, most α2C-selective antagonist (0.15nM α2C-affinity) although its α2C-selectivity is only 13-fold greater than at α2A. There are no truely α2B-selective antagonists. A few α-ligands with significant β-affinity were detected, for example, naftopidil where its clinical α1A-affinity is only 3-fold greater than off-target β2-affinity. Antidepressants (except mirtazapine) and first-generation antipsychotics have higher α1A than α2-adrenoceptor affinity but poor β-affinity. Second-generation antipsychotics varied widely in their α2-adrenoceptor affinity. Risperidone (9nM) and paliperidone (14nM) have the highest α2C-adrenoceptor affinity however this is only 5-fold selective over α2A, and both have a higher affinity for α1A (2nM and 4nM, respectively). So, despite a century of yohimbine use, and decades of α2-subtype studies, there remains plenty of scope to develop α2-subtype selective antagonists.

Citation

Proudman, R. G. W., Akinaga, J., & Baker, J. G. (2022). The affinity and selectivity of α-adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C-adrenoceptors and comparison with human α1 and β-adrenoceptors. Pharmacology Research and Perspectives, 10(2), Article e00936. https://doi.org/10.1002/prp2.936

• Journal Article Type: Article
• Acceptance Date: Jan 20, 2022
• Online Publication Date: Feb 27, 2022
• Publication Date: 2022-04
• Deposit Date: Jan 21, 2022
• Publicly Available Date: Jan 21, 2022
• Journal: Pharmacology Research & Perspectives
• Electronic ISSN: 2052-1707
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 2
• Article Number: e00936
• DOI: https://doi.org/10.1002/prp2.936
• Keywords: General Pharmacology, Toxicology and Pharmaceutics; Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/7282938
• Publisher URL: https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.936