A series of novel substituted beta-carbolines was synthesized and tested for potential antipsychotic activity. Several compounds displayed moderate antipsychotic activity in vitro and in vivo as determined by relevant receptor binding assays and behavioral tests. The effect of substituents on antipsychotic activity was examined. The beta-carbolines 10 and 19 containing 2-(2-pyridinyl)ethyl and 2-(2-quinolinyl)ethyl side chains were the most potent analogues, blocking discrete trial conditioned avoidance responding in rats with AB50's of 23 and 10 mg/kg, respectively. Both showed moderate activity at the D2 receptor sites, but they lacked oral activity. In contrast, the beta-carboline 13 containing the 4-(4-pyridinyl)butyl side chain exhibited oral activity in the discrete trial conditioned avoidance screen with an AB50 of 31 mg/kg. Most compounds did not antagonize apomorphine-induced stereotyped behavior, which is indicative of low potential for extrapyramidal side effect (EPS) liability.