Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M5 PAM

Thomas M. Bridges, J. Phillip Kennedy, Hyekyung P. Cho, Micah L. Breininger, Patrick R. Gentry, Corey R. Hopkins, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1-M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS.

Original languageEnglish (US)
Pages (from-to)558-562
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number2
DOIs
StatePublished - Jan 15 2010

Keywords

  • Allosteric
  • M5
  • Muscarinic receptor
  • PAM
  • Positive allosteric modualtor

ASJC Scopus subject areas

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

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