Ligand bias and inverse agonism on 5‐HT2A receptor‐mediated modulation of G protein activity in post‐mortem human brain

Abstract

AbstractBackground and PurposeWhereas biased agonism on the 5‐HT2A receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5‐HT2A 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‐HT2A receptor antagonists, in post‐mortem human brain cortex.Experimental ApproachModulation of [35S]GTPγS binding to different subtypes of Gα proteins exerted by different 5‐HT2A receptor drugs was determined by scintillation proximity assays in brain from human, WT and 5‐HT2A receptor KO mice.Key ResultsMDL‐11,939 was the only drug having no effect on the basal activity of 5‐HT2A receptor. Altanserin and pimavanserin decreased basal activation of Gi1, but not Gq/11 proteins. This effect was blocked by MDL‐11,939 and absent in 5‐HT2A receptor KO mice. Volinanserin showed 5‐HT2A receptor‐mediated inverse agonism both on Gi1 and Gq/11 proteins. Ketanserin exhibited 5‐HT2A receptor partial agonism exclusively on Gq/11 proteins. On the other hand, eplivanserin and nelotanserin displayed inverse agonism on Gq/11 and/or Gi1 proteins, which was insensitive to MDL‐11,939 and was present in KO mice suggesting a role for another receptor.Conclusion and ImplicationsThe results reveal the existence of constitutively active 5‐HT2A receptors in human pre‐frontal cortex and demonstrate different pharmacological profiles of various 5‐HT2A receptor drugs previously considered antagonists. These findings indicate that altanserin and pimavanserin possess biased inverse agonist profile towards 5‐HT2A receptor activation of Gi1 proteins.