Behavioral Approach to Nondyskinetic Dopamine Antagonists:  Identification of Seroquel

Abstract

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 1 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.

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

“…All of the compounds have been described in patent applications, although the synthesis of compound 21 has never been reported. Surprisingly, no peer-reviewed biological data have been reported with compounds 5, 13, 15, 21, or 23 (Burki et al, 1977(Burki et al, , 1978Grimm et al, 2006;Kalhapure et al, 2011;Schmutz, 1975;Smits et al, 2006;Warawa et al, 2001).…”

Reinvestigation of alternative method for the preparation of dibenz[b,f][1,4]oxazepine

“…Dibenz[b,f] [1,4]oxazepine (7,CR) is an incapacitating lachrymatory agent [1][2][3][4][5][6] and is an intermediate in the synthesis of loxapine (antipsychotic), amoxapine (antidepressant) [7], and others substituted dibenzoxazepine compounds that are analgesic or useful for the treatment of different diseases [8][9][10][11].…”

Improved etherification procedure for the preparation of dibenz[b,f][1,4]oxazepine

“…It is chemically related to loxapine (antipsychotic), amoxapine (antidepressant) [7] and others substituted dibenzoxazepine compounds that are analgesic or useful for the treatment of various diseases [8][9][10]. There are different methods for the preparation of this compound [11][12][13][14][15][16][17][18][19].…”