Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M5 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 M₁, M₃, M₅ positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M₅ 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

Research output: Contribution to journal › Article

35 Scopus citations

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 (US)
Pages (from-to)	558-562
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2009.11.089
State	Published - Jan 15 2010

Keywords

Allosteric
M5
Muscarinic receptor
PAM
Positive allosteric modualtor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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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 M₁, M₃, M₅ positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M₅ PAM. Bioorganic and Medicinal Chemistry Letters, 20(2), 558-562. https://doi.org/10.1016/j.bmcl.2009.11.089

Chemical lead optimization of a pan G_q mAChR M₁, M₃, M₅ positive allosteric modulator (PAM) lead. Part I : Development of the first highly selective M₅ PAM. / Bridges, Thomas M.; Kennedy, J. Phillip; Cho, Hyekyung P.; Breininger, Micah L.; Gentry, Patrick R.; Hopkins, Corey R.; Conn, P. Jeffrey; Lindsley, Craig W.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 2, 15.01.2010, p. 558-562.

Research output: Contribution to journal › Article

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 M₁, M₃, M₅ positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M₅ PAM', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 2, pp. 558-562. https://doi.org/10.1016/j.bmcl.2009.11.089

Bridges, Thomas M. ; Kennedy, J. Phillip ; Cho, Hyekyung P. ; Breininger, Micah L. ; Gentry, Patrick R. ; Hopkins, Corey R. ; Conn, P. Jeffrey ; Lindsley, Craig W. / Chemical lead optimization of a pan G_q mAChR M₁, M₃, M₅ positive allosteric modulator (PAM) lead. Part I : Development of the first highly selective M₅ PAM. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 2. pp. 558-562.

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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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