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

BACKGROUND AND PURPOSE

Whereas biased agonism on the 5-HT 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 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 receptor antagonists, in post-mortem human brain cortex.

EXPERIMENTAL APPROACH

Modulation of [S]GTPγS binding to different subtypes of Gα proteins exerted by different 5-HT receptor drugs was determined by scintillation proximity assays in brain from human, WT and 5-HT receptor KO mice.

KEY RESULTS

MDL-11,939 was the only drug having no effect on the basal activity of 5-HT receptor. Altanserin and pimavanserin decreased basal activation of G, but not G proteins. This effect was blocked by MDL-11,939 and absent in 5-HT receptor KO mice. Volinanserin showed 5-HT receptor-mediated inverse agonism both on G and G proteins. Ketanserin exhibited 5-HT receptor partial agonism exclusively on G proteins. On the other hand, eplivanserin and nelotanserin displayed inverse agonism on G and/or G 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 receptors in human pre-frontal cortex and demonstrate different pharmacological profiles of various 5-HT receptor drugs previously considered antagonists. These findings indicate that altanserin and pimavanserin possess biased inverse agonist profile towards 5-HT receptor activation of G proteins.