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

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

doi:10.1016/j.bmcl.2009.11.089

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

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

36 Citations (Scopus)

Abstract

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M₅-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G_q mAChR M₁, M₃, M₅ PAM. An iterative library synthesis approach delivered the first selective M₅ PAM (no activity at M₁-M₄ @ 30 μM), and an important tool compound to study the role of M₅ in the CNS.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	20
Issue number	2
Pages (from-to)	558-62
Number of pages	5
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2009.11.089
Publication status	Published - 15 Jan 2010
Externally published	Yes

Keywords

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

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Bridges, T. M., Kennedy, J. P., Cho, H. P., Breininger, M. L., Gentry, P. R., Hopkins, C. R., Conn, P. J., & Lindsley, C. W. (2010). 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. Bioorganic & Medicinal Chemistry Letters, 20(2), 558-62. https://doi.org/10.1016/j.bmcl.2009.11.089

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, Thomas M; Kennedy, J Phillip; Cho, Hyekyung P et al.

In: Bioorganic & Medicinal Chemistry Letters, Vol. 20, No. 2, 15.01.2010, p. 558-62.

Research output: Contribution to journal › Journal article › Research › peer-review

Bridges, TM, Kennedy, JP, Cho, HP, Breininger, ML, Gentry, PR, Hopkins, CR, Conn, PJ & Lindsley, CW 2010, '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', Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 2, pp. 558-62. https://doi.org/10.1016/j.bmcl.2009.11.089

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abstract = "This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1-M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS.",

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AU - Bridges, Thomas M

AU - Kennedy, J Phillip

AU - Cho, Hyekyung P

AU - Breininger, Micah L

AU - Gentry, Patrick R

AU - Hopkins, Corey R

AU - Conn, P Jeffrey

AU - Lindsley, Craig W

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AB - This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1-M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS.

KW - Allosteric Regulation

KW - Animals

KW - CHO Cells

KW - Cricetinae

KW - Cricetulus

KW - Drug Design

KW - High-Throughput Screening Assays

KW - Mice

KW - Mice, Knockout

KW - Receptor, Muscarinic M1/agonists

KW - Receptor, Muscarinic M3/agonists

KW - Receptor, Muscarinic M5/agonists

KW - Structure-Activity Relationship

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DO - 10.1016/j.bmcl.2009.11.089

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EP - 562

JO - Bioorganic & Medicinal Chemistry Letters

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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

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Keywords

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