Behavioral approach to nondyskinetic dopamine antagonists: Identification of seroquel

A great need exists for antipsychotic drugs which will not induce extrapyra midal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and me solimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potenc y D2 dopamine receptor antagonist which appears to act selectively in the m esolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonis m of apomorphine-induced disruption of swimming. The potential for the liab ility of dyskinesias was determined in haloperidol-sensitized Cebus monkeys . Initial examination of a few close cogeners of 1 enhanced confidence in t he Cebus model as a predictor of dyskinetic potential. Considering dibenzaz epines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazep ines, 1 did not induce dyskinesias where as its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-y l)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepi nes and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy) ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an ap omorphine antagonist comparable to clozapine. It was essentially nondyskine tic in the Cebus model. With 23 as a platform, a number of N-substituted an alogues were found to be good apomorphine antagonists but all were dyskinet ic.