Pimavanserin exhibits serotonin 5-HT2A receptor inverse agonism for Gαi1- and neutral antagonism for Gαq/11-proteins in human brain cortex

Pimavanserin is claimed as the first antipsychotic drug that shows selectivity for serotonin 5-HT2 receptors (5-HT(2)Rs) and lacks of affinity for dopamine D-2 receptors (D(2)Rs). Cell-based functional assays suggest that pimavanserin and antipsychotics with D2R/5-HT2R 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(alpha q/11)- and non-canonical G(alpha i1)-proteins. In the present study, the response to pimavanserin of the 5-HT2AR coupling to G(alpha q/11) - and G(alpha i1)-proteins was measured in membranes of postmortem human prefrontal cortex by antibody-capture [S-35]GTP gamma S binding scintillation proximity assays. Pimavanserin promoted a concentration-dependant inhibition of the 5-HT2AR coupling to G(alpha i1)-proteins whereas the response of G(alpha q/11)-proteins was unaltered, suggesting inverse agonism and neutral antagonism properties, respectively. The inhibition was abolished in the presence of the selective 5-HT2AR antagonist MDL-11,939 and was absent in brain cortex of 5-HT2AR knock-out mice when compared to respective 5-HT2AR wild-type animals. In conclusion, the results demonstrate the existence of constitutive 5-HT2AR activity in human brain for the signalling pathway mediated by G(alpha i1)-proteins. Pimavanserin demonstrates 5-HT2AR functional selectivity and exhibits inverse agonist profile towards G(alpha i1)-proteins, which is considered the effector pathway promoting hallucinogenic responses. In contrast, pimavanserin behaves as neutral antagonist on the 5-HT2AR coupling to the canonical G(alpha q/11)-protein pathway. The results strengthen the relevance of in-verse agonism as potential mechanism of antipsychotic activity. Moreover, the existence of functional selectivity of 5-HT(2A)Rs for different G(alpha)-proteins could contribute to better design of 5-HT2AR-related antipsychotic drugs. (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)