Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.

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A series of benzisoxazole- and benzisothiazole-3-carboxamides has been prepared and tested for potential antipsychotic activity. In general, the compounds showed an affinity for dopamine D2 and serotonin 5HT2A and 5HT1A receptors. Several members of this series have demonstrated activity in animal models predictive of potential antipsychotic activity. In addition, compounds 18, 19, 22, 27, 28, 43, and 44 have also shown a potential for reduced EPS liability as suggested by the ratio of activity seen in mesolimbic-mediated vs nigrostriatal-mediated behavioral assays.

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