Pimavanserin exhibits serotonin 5-HT 2A receptor inverse agonism for G αi1 - and neutral antagonism for G αq/11 -proteins in human brain cortex

Abstract

[EN] Pimavanserin is claimed as the first antipsychotic drug that shows selectivity for serotonin 5- HT 2 receptors (5-HT 2 Rs) and lacks of affinity for dopamine D 2 receptors (D 2 Rs). Cell-based func- tional assays suggest that pimavanserin and antipsychotics with D 2 R/5-HT 2 R affinity could act as inverse agonists of 5-HT 2A Rs. However, there is not evidence of such pharmacological profile in native brain tissue. 5-HT 2A Rs are able to engage both canonical G αq/11 - and non-canonical G αi1 -proteins. In the present study, the response to pimavanserin of the 5-HT 2A R coupling to G αq/11 - and G αi1 -proteins was measured in membranes of postmortem human prefrontal cortex by antibody-capture [ 35 S]GTP γS binding scintillation proximity assays. Pimavanserin promoted a concentration-dependant inhibition of the 5-HT 2A R coupling to G αi1 -proteins whereas the re- sponse of G αq/11 -proteins was unaltered, suggesting inverse agonism and neutral antagonism properties, respectively. The inhibition was abolished in the presence of the selective 5-HT 2A R antagonist MDL-11,939 and was absent in brain cortex of 5-HT 2A R knock-out mice when com- pared to respective 5-HT 2A R wild-type animals. In conclusion, the results demonstrate the ex- istence of constitutive 5-HT 2A R activity in human brain for the signalling pathway mediated by G αi1 -proteins. Pimavanserin demonstrates 5-HT 2A R functional selectivity and exhibits inverse agonist profile towards G αi1 -proteins, which is considered the effector pathway promoting hal- lucinogenic responses. In contrast, pimavanserin behaves as neutral antagonist on the 5-HT 2A R coupling to the canonical G αq/11 -protein pathway. The results strengthen the relevance of inverse agonism as potential mechanism of antipsychotic activity. Moreover, the existence of functional selectivity of 5-HT 2A Rs for different G α-proteins could contribute to better design of 5-HT 2A R-related antipsychotic drugs.