Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM

Bioorg Med Chem Lett. 2010 Jan 15;20(2):558-62. doi: 10.1016/j.bmcl.2009.11.089. Epub 2009 Nov 22.


This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Design
  • High-Throughput Screening Assays
  • Mice
  • Mice, Knockout
  • Receptor, Muscarinic M1 / agonists
  • Receptor, Muscarinic M1 / chemistry
  • Receptor, Muscarinic M1 / metabolism*
  • Receptor, Muscarinic M3 / agonists
  • Receptor, Muscarinic M3 / metabolism*
  • Receptor, Muscarinic M5 / agonists
  • Receptor, Muscarinic M5 / metabolism*
  • Structure-Activity Relationship


  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M3
  • Receptor, Muscarinic M5