Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins

Thomas M Bridges; Joy E Marlo; Colleen M Niswender; Carrie K Jones; Satyawan B Jadhav; Patrick R Gentry; Hyekyung C Plumley; C David Weaver; P Jeffrey Conn; Craig W Lindsley

doi:10.1021/jm900286j

Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins

Thomas M Bridges, Joy E Marlo, Colleen M Niswender, Carrie K Jones, Satyawan B Jadhav, Patrick R Gentry, Hyekyung C Plumley, C David Weaver, P Jeffrey Conn, Craig W Lindsley

79 Citationer (Scopus)

Abstract

This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	52
Udgave nummer	11
Sider (fra-til)	3445-8
Antal sider	4
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm900286j
Status	Udgivet - 11 jun. 2009
Udgivet eksternt	Ja

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10.1021/jm900286j

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Bridges, T. M., Marlo, J. E., Niswender, C. M., Jones, C. K., Jadhav, S. B., Gentry, P. R., Plumley, H. C., Weaver, C. D., Conn, P. J., & Lindsley, C. W. (2009). Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. Journal of Medicinal Chemistry, 52(11), 3445-8. https://doi.org/10.1021/jm900286j

Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. / Bridges, Thomas M; Marlo, Joy E; Niswender, Colleen M et al.

I: Journal of Medicinal Chemistry, Bind 52, Nr. 11, 11.06.2009, s. 3445-8.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Bridges, TM, Marlo, JE, Niswender, CM, Jones, CK, Jadhav, SB, Gentry, PR, Plumley, HC, Weaver, CD, Conn, PJ & Lindsley, CW 2009, 'Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins', Journal of Medicinal Chemistry, bind 52, nr. 11, s. 3445-8. https://doi.org/10.1021/jm900286j

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abstract = "This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.",

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AU - Marlo, Joy E

AU - Niswender, Colleen M

AU - Jones, Carrie K

AU - Jadhav, Satyawan B

AU - Gentry, Patrick R

AU - Plumley, Hyekyung C

AU - Weaver, C David

AU - Conn, P Jeffrey

AU - Lindsley, Craig W

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AB - This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.

KW - Allosteric Regulation/physiology

KW - Animals

KW - CHO Cells

KW - Cricetinae

KW - Cricetulus

KW - Isatin/analogs & derivatives

KW - Mice

KW - Receptor, Muscarinic M5/drug effects

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Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins

Abstract

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