SYNTHESIS AND EVALUATION OF HETEROCYCLIC CARBOXAMIDES AS POTENTIAL ANTIPSYCHOTIC AGENTS

Heterocyclic analogues of 1192U90, -N-(4-(4-(1,2-benzisothiazol-3-yl)- 1-piperazinyl)- butyl)benzamide hydrochloride (1), were prepared and e valuated as potential antipsychotic agents. These analogues were evalu ated in vitro for their binding to the dopamine D-2, serotonin 5-HT2, and serotonin 5-HTL(1a) receptors and in vivo for their ability to ant agonize the apomorphine-induced climbing response in mice. Nine differ ent types of heterocyclic carboxamides were studied in this investigat ion (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4 -tetrahydroquinoline-,2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarbox-amides), Two derivatives exhibited potent in vivo acti vities comparable to 1: l-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxa mide (16) and -3-yl)-1-piperazinyl)butyl)-2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in b ehavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxam ides 16 and 29 were selected for further evaluation as potential backu p compounds to 1.