Chemical modification of ring c of himbacine: Discovery of a pharmacophoric element for M2-selectivity

Michael J. Malaska, Abdul H. Fauq, Alan P. Kozikowski, Patricia J. Aagaard, Michael McKinney

Research output: Contribution to journalArticle

Abstract

Removal of the carbonyl oxygen of himbacine furnishes a molecule which binds with 20-fold and 4-fold lower affinity at the M2 and M1 receptor sites, respectively. Thus, the carbonyl oxygen constitutes an important pharmacophoric element responsible for some of the M2 selectivity of himbacine. Other modifications of the C-ring of the tricyclic portion of himbacine were examined and tested for potency at M1 and M2 sites, and the data confirm that M2 selectivity is optimal with a closed heterocyclic ring and with the presence of a proximal carbonyl oxygen.

Original languageEnglish (US)
Pages (from-to)61-66
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume5
Issue number1
DOIs
StatePublished - Jan 5 1995

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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