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.