2. Academic Validation
  3. 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

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.
Thomas M Bridges 1,  Joy E Marlo,  Colleen M Niswender,  Carrie K Jones,  Satyawan B Jadhav,  Patrick R Gentry,  Hyekyung C Plumley,  C David Weaver,  P Jeffrey Conn,  Craig W Lindsley
Affiliations

Affiliation

  • 1 Vanderbilt Program in Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232-0697, USA.
PMID: 19438238 DOI: 10.1021/jm900286j
Abstract

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.

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