STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF SUBSTITUTED BENZAMIDES - POTENT D-2 5-HT2 ANTAGONISTS AND 5-HT1A AGONISTS AS NEUROLEPTIC AGENTS/

A series of substituted benzisothiazol-3-yl)-1-piperazinyl)butyl)benza mide derivatives was prepared and evaluated as potential atypical anti psychotic agents. The target compounds were readily prepared from thei r benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D- 2, serotonin 5-HT2, and serotonin 5-HT1a, receptors. To assess the pot ential antipsychotic activity of these compounds, we investigated thei r ability to inhibit the apomorphine-induced climbing response in mice . Selected compounds were evaluated further to determine their side-ef fect potentials. Structure-activity relationships of both mono- and po lysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential at ypical antipsychotic activity, anthranilamide 77 (1192U90) demonstrate d a superior pharmacological profile. As a result of this investigatio n, 1192U90 -(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) benzamid e hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent .