title: Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
abstract: Variable-temperature proton nuclear magnetic resonance studies have shown that 5-(2-propylidene)-10-(4-methylpiperazino)-5H-dibenzo[a,d] cycloheptene, a 5,11-dicarbo analogue of the atypical neuroleptic agent clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine], exists as thermally stable configurational isomers. The presence of the 2-propylidene group at C-5 on the 5H-dibenzo[a,d]cycloheptene moiety did not interfere greatly, as compared to clozapine, with the in vitro affinity of this 5,11-dicarbo analogue of clozapine for muscarinic and dopamine D-1 and D-2 binding sites in rat brain. Since the presence and position of a chloro substituent on the 5H-dibenzo[b,e][1,4]diazepine moiety have a marked influence on the respective binding affinities of 1,4-diazepines related to clozapine, chloro-substituted 5,11-dicarbo analogues of clozapine were prepared in order to further examine structure-activity relationships. Evaluation of these analogues for binding to muscarinic and dopamine binding sites in comparison with clozapine and other 5H-dibenzo[b,e][1,4]diazepine analogues of clozapine shows that the dopamine D-1 and D-2 receptor affinities of both the 5-(2-propylidene)-5,11-dicarbo analogue and its corresponding distal-chloro derivative, 2-chloro-5-(2-propylidene)-10-(4-methylpiperazino)-5H- dibenzo[a,d]cycloheptene, are retained. Because of the susceptibility to acid-catalyzed hydrolysis of these tertiary enamines, however, these compounds serve only as model compounds for their structure-activity evaluation. Since the proximal nitrogen atom of the piperazine ring is redundant for biological activity, 5-(2-propylidene)-10-(1-methyl-4-pyridyl)-5H-dibenzo[a,d]cycloh eptene and its 2-chloro derivative are excellent candidates for resolution into enantiomers as a means to separate antimuscarinic and antidopaminergic activity, respectively, associated with only a single stereoisomer.
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: D A
authors.initials: DA
authors.lastname: Davis
authors.forename: T
authors.initials: T
authors.lastname: de Paulis
authors.forename: A
authors.initials: A
authors.lastname: Janowsky
authors.forename: H E
authors.initials: HE
authors.lastname: Smith
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003024:Clozapine / Q000031:analogs & derivatives* / Q000378:metabolism; D003984:Dibenzazepines; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009038:Motion; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D003984:Dibenzazepines; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D003024:Clozapine