Synthesis and evaluation of amide, sulfonamide and urea - benzisoxazole derivatives as potential atypical antipsychotics

In this paper, we report the optimization of a series of novel, potential antipsychotic derivatives combining potent dopamine D-2, D-3 and serotonin 5-HT1A, 5-HT2A receptor affinities. The pharmacological features of compound 27 are a high affinity for dopamine D-2, D-3 and serotonin 5-HT1A, 5-HT2A receptors. Moreover it possesses low affinity for 5-HT2C and H-1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). Furthermore, compound 27 inhibited apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitch without observable catalepsy at the highest dose tested in mice. Taken together, among the amide derivatives, we identified compound 27 as a potential antipsychotic lead candidate.