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

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

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.

Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Volume20
Issue number2
Pages (from-to)558-62
Number of pages5
ISSN0960-894X
DOIs
Publication statusPublished - 15 Jan 2010
Externally publishedYes

Bibliographical note

Copyright 2009 Elsevier Ltd. All rights reserved.

    Research areas

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

ID: 213627032