Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics.

Abstract The present study describes the optimization of a series of novel benzoxazole–piperidine (piperazine) derivatives combining high dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D 2 , 5-HT 1A and 5-HT 2A receptors, but low affinities for the 5-HT 2C and histamine H 1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.