Ligand bias and inverse agonism on 5-HT 2A receptor-mediated modulation of G protein activity in post-mortem human brain.

Autor: Muneta-Arrate I; Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Spain.; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, ISCIII, Leioa, Spain.; Current address: Department of Basic Neuroscience, Medical Faculty, University of Geneva, Geneva, Switzerland., Miranda-Azpiazu P; Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Spain.; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, ISCIII, Leioa, Spain., Horrillo I; Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Spain.; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, ISCIII, Leioa, Spain.; Biobizkaia Health Research Institute, Barakaldo, Spain., Diez-Alarcia R; Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Spain.; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, ISCIII, Leioa, Spain.; Biobizkaia Health Research Institute, Barakaldo, Spain., Meana JJ; Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Spain.; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, ISCIII, Leioa, Spain.; Biobizkaia Health Research Institute, Barakaldo, Spain.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Apr 21. Date of Electronic Publication: 2024 Apr 21.
DOI: 10.1111/bph.16368
Abstrakt: Background and Purpose: Whereas biased agonism on the 5-HT 2A receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5-HT 2A receptor constitutive activity has been suggested, highlighting the therapeutic relevance of inverse agonism. This study characterized the modulation of G protein activity promoted by different drugs, commonly considered as 5-HT 2A receptor antagonists, in post-mortem human brain cortex.
Experimental Approach: Modulation of [ 35 S]GTPγS binding to different subtypes of Gα proteins exerted by different 5-HT 2A receptor drugs was determined by scintillation proximity assays in brain from human, WT and 5-HT 2A receptor KO mice.
Key Results: MDL-11,939 was the only drug having no effect on the basal activity of 5-HT 2A receptor. Altanserin and pimavanserin decreased basal activation of G i1 , but not G q/11 proteins. This effect was blocked by MDL-11,939 and absent in 5-HT 2A receptor KO mice. Volinanserin showed 5-HT 2A receptor-mediated inverse agonism both on G i1 and G q/11 proteins. Ketanserin exhibited 5-HT 2A receptor partial agonism exclusively on G q/11 proteins. On the other hand, eplivanserin and nelotanserin displayed inverse agonism on G q/11 and/or G i1 proteins, which was insensitive to MDL-11,939 and was present in KO mice suggesting a role for another receptor.
Conclusion and Implications: The results reveal the existence of constitutively active 5-HT 2A receptors in human pre-frontal cortex and demonstrate different pharmacological profiles of various 5-HT 2A receptor drugs previously considered antagonists. These findings indicate that altanserin and pimavanserin possess biased inverse agonist profile towards 5-HT 2A receptor activation of G i1 proteins.
(© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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