Synthesis and evaluation of heterocyclic carboxamides as potential antipsychotic agents

Journal of Medicinal Chemistry
M H NormanG C Rigdon

Abstract

Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl) benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-, 2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarboxamides). Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2 -pyridinecarboxamide (16) and 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) -2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.

Citations

Aug 13, 2011·Chemical Reviews·Vellaisamy SridharanJ Carlos Menéndez
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·I D KuntzP A Kollman
May 28, 2015·Organic & Biomolecular Chemistry·Mark C BagleyNicholas C O Tomkinson
Mar 21, 2012·Chemical Communications : Chem Comm·Jiangling PengQiang Zhu

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