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 Citations (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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	11
Pages (from-to)	3445-8
Number of pages	4
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm900286j
Publication status	Published - 11 Jun 2009
Externally published	Yes

Keywords

Allosteric Regulation/physiology
Animals
CHO Cells
Cricetinae
Cricetulus
Isatin/analogs & derivatives
Mice
Receptor, Muscarinic M5/drug effects

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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.
In: Journal of Medicinal Chemistry, Vol. 52, No. 11, 11.06.2009, p. 3445-8.

Research output: Contribution to journal › Journal article › Research › 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, vol. 52, no. 11, pp. 3445-8. https://doi.org/10.1021/jm900286j

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title = "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 = "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.",

keywords = "Allosteric Regulation/physiology, Animals, CHO Cells, Cricetinae, Cricetulus, Isatin/analogs & derivatives, Mice, Receptor, Muscarinic M5/drug effects",

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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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DO - 10.1021/jm900286j

M3 - Journal article

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JO - Journal of Medicinal Chemistry

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ER -

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

Keywords

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