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

European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology
Itziar Muneta-ArrateJ Javier Meana

Abstract

Pimavanserin is claimed as the first antipsychotic drug that shows selectivity for serotonin 5-HT2 receptors (5-HT2Rs) and lacks of affinity for dopamine D2 receptors (D2Rs). Cell-based functional assays suggest that pimavanserin and antipsychotics with D2R/5-HT2R affinity could act as inverse agonists of 5-HT2ARs. However, there is not evidence of such pharmacological profile in native brain tissue. 5-HT2ARs are able to engage both canonical Gαq/11- and non-canonical Gαi1-proteins. In the present study, the response to pimavanserin of the 5-HT2AR coupling to Gαq/11- and Gαi1-proteins was measured in membranes of postmortem human prefrontal cortex by antibody-capture [35S]GTPγS binding scintillation proximity assays. Pimavanserin promoted a concentration-dependant inhibition of the 5-HT2AR coupling to Gαi1-proteins whereas the response of Gαq/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...Continue Reading

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