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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.

Bridges TM, Kennedy JP, Cho HP, Breininger ML, Gentry PR, Hopkins CR, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2010 20 (2): 558-62

PMID: 20004578 · PMCID: PMC3177601 · DOI:10.1016/j.bmcl.2009.11.089

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.

Copyright 2009 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

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

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