Discovery of a selective M4 positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia

Uyen Le; Bruce J. Melancon; Thomas M. Bridges; Paige N. Vinson; Thomas J. Utley; Atin Lamsal; Alice L. Rodriguez; Daryl Venable; Douglas J. Sheffler; Carrie K. Jones; Anna L. Blobaum; Michael R. Wood; J. Scott Daniels; P. Jeffrey Conn; Colleen M. Niswender; Craig W. Lindsley; Corey R. Hopkins

doi:10.1016/j.bmcl.2012.10.073

Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia

Uyen Le, Bruce J. Melancon, Thomas M. Bridges, Paige N. Vinson, Thomas J. Utley, Atin Lamsal, Alice L. Rodriguez, Daryl Venable, Douglas J. Sheffler, Carrie K. Jones, Anna L. Blobaum, Michael R. Wood, J. Scott Daniels, P. Jeffrey Conn, Colleen M. Niswender, Craig W. Lindsley, Corey R. Hopkins

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

Herein we report a next generation muscarinic receptor 4 (M₄) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC₅₀ = 56 nM) and rat (EC₅₀ = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.

Original language	English (US)
Pages (from-to)	346-350
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2012.10.073
State	Published - Jan 1 2013
Externally published	Yes

Keywords

Amphetamine induced hyperlocomotion
CNS
Muscarinic receptor 4
PAM
Positive allosteric modulator

ASJC Scopus subject areas

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

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Le, U., Melancon, B. J., Bridges, T. M., Vinson, P. N., Utley, T. J., Lamsal, A., Rodriguez, A. L., Venable, D., Sheffler, D. J., Jones, C. K., Blobaum, A. L., Wood, M. R., Daniels, J. S., Conn, P. J., Niswender, C. M., Lindsley, C. W., & Hopkins, C. R. (2013). Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia. Bioorganic and Medicinal Chemistry Letters, 23(1), 346-350. https://doi.org/10.1016/j.bmcl.2012.10.073

Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia. / Le, Uyen; Melancon, Bruce J.; Bridges, Thomas M. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 1, 01.01.2013, p. 346-350.

Research output: Contribution to journal › Article › peer-review

Le, U, Melancon, BJ, Bridges, TM, Vinson, PN, Utley, TJ, Lamsal, A, Rodriguez, AL, Venable, D, Sheffler, DJ, Jones, CK, Blobaum, AL, Wood, MR, Daniels, JS, Conn, PJ, Niswender, CM, Lindsley, CW & Hopkins, CR 2013, 'Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 1, pp. 346-350. https://doi.org/10.1016/j.bmcl.2012.10.073

Le U, Melancon BJ, Bridges TM, Vinson PN, Utley TJ, Lamsal A et al. Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia. Bioorganic and Medicinal Chemistry Letters. 2013 Jan 1;23(1):346-350. doi: 10.1016/j.bmcl.2012.10.073

Le, Uyen ; Melancon, Bruce J. ; Bridges, Thomas M. et al. / Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold : Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 1. pp. 346-350.

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abstract = "Herein we report a next generation muscarinic receptor 4 (M4) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC50 = 56 nM) and rat (EC50 = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.",

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