Igor Horrillo

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.