Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics

Abstract In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D 2 , serotonin 5-HT 1A and 5-HT 2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[ b ]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2- a ]pyrimidin-4-one ( 10d ) held the best pharmacological profile. It not only exhibited potent and balanced activities for D 2 , 5-HT 1A , and 5-HT 2A receptors, but was also endowed with low activities for α 1A , 5-HT 2C , H 1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.