Chloro-Substituted, Sterically Hindered 5,11-Dicarbo Analogues of Clozapine as Potential Chiral Antipsychotic Agents

Daniel A. Davis, Tomas de Paulis, Howard E. Smith, Aaron Janowsky

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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-ll-(4-methylpiperazino)-5.H-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-2 and D-2 receptor affinities of both the 5-(2-propylidene)-5,ll-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-(l-methyl-4-pyridyl)-5H-dibenzo[a,d]-cycloheptene 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.

Original languageEnglish (US)
Pages (from-to)809-814
Number of pages6
JournalJournal of Medicinal Chemistry
Volume33
Issue number2
DOIs
StatePublished - Feb 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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