title: 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.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca Pharmaceuticals LP, Wilmington, Delaware 19850-5437, USA. kcassoc@inet.net
authors.forename: E J
authors.initials: EJ
authors.lastname: Warawa
authors.forename: B M
authors.initials: BM
authors.lastname: Migler
authors.forename: C J
authors.initials: CJ
authors.lastname: Ohnmacht
authors.forename: A L
authors.initials: AL
authors.lastname: Needles
authors.forename: G C
authors.initials: GC
authors.lastname: Gatos
authors.forename: F M
authors.initials: FM
authors.lastname: McLaren
authors.forename: C L
authors.initials: CL
authors.lastname: Nelson
authors.forename: K M
authors.initials: KM
authors.lastname: Kirkland
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002428:Cebus; D003987:Dibenzothiazepines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D005260:Female; D008297:Male; D051379:Mice; D000069348:Quetiapine Fumarate; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D000069348:Quetiapine Fumarate; D001058:Apomorphine