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

MedChemComm Pub Date: 2015-02-13 DOI: 10.1039/C4MD00578C

Abstract

In this paper, we report the optimization of a series of novel, potential antipsychotic derivatives combining potent dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptor affinities. The pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors. Moreover it possesses low affinity for 5-HT2C and H1 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.

Graphical abstract: Synthesis and evaluation of amide, sulfonamide and urea – benzisoxazole derivatives as potential atypical antipsychotics
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