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

J Med Chem. 2009 Jun 11;52(11):3445-8. doi: 10.1021/jm900286j.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Receptor, Muscarinic M5
  • VU 01119498
  • Isatin