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 › peer-review

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
Externally published	Yes

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 › 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 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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author = "Bridges, {Thomas M.} and Kennedy, {J. Phillip} and Cho, {Hyekyung P.} and Breininger, {Micah L.} and Gentry, {Patrick R.} and Hopkins, {Corey R.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.}",

note = "Funding Information: The authors thank NIMH (1RO1 MH082867), NIH, the MLPCN (1U54 MH084659) and the Alzheimer{\textquoteright}s Association (IIRG-07-57131) for support of our Program in the development of subtype selective allosteric ligands of mAChRs. ",

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AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

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