329217-05-2Relevant articles and documents
Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel
Warawa,Migler,Ohnmacht,Needles,Gatos,McLaren,Nelson,Kirkland
, p. 372 - 389 (2007/10/03)
A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-Potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-Induced climbing and antagonism of apomorphine-Induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-Sensitized Cebus monkeys. Initial examination of a few close cogeners of I enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas 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-yl)-11H-Dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]-thiazepines 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 apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-Substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.
