Increased release of dopamine in vivo by BMY-14802: contrasting pattern to clozapine

In preclinical studies, BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-l-piperazine-buta nol], a potent sigma ligand, exhibited a profile similar to clozapine, an atypical antipsychotic agent. Several atypical antipsychotics have previously been demonstrated to increase dopamine (DA) metabolism without altering DA release in vivo, suggesting a potential mechanism for their lack of extrapyramidal side effects. BMY-14802 increased DA metabolism and release while clozapine increased DA metabolism but decreased DA release in the mouse. This is the first demonstration of a sigma ligand mediated DA release in vivo. The lack of extrapyramidal side effects, despite the enhanced DA release in vivo after BMY-14802 suggests that the atypical profile of clozapine can not be explained by its depressant actions on DA release alone.