Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins

Research output: Contribution to journalJournal articleResearchpeer-review

  • Thomas M Bridges
  • Joy E Marlo
  • Colleen M Niswender
  • Carrie K Jones
  • Satyawan B Jadhav
  • Gentry, Patrick Ryan
  • Hyekyung C Plumley
  • C David Weaver
  • P Jeffrey Conn
  • Craig W Lindsley

This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number11
Pages (from-to)3445-8
Number of pages4
Publication statusPublished - 11 Jun 2009
Externally publishedYes

    Research areas

  • Allosteric Regulation/physiology, Animals, CHO Cells, Cricetinae, Cricetulus, Isatin/analogs & derivatives, Mice, Receptor, Muscarinic M5/drug effects

ID: 213627227