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 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
Bioorg Med Chem Lett. 2013 23 (1): 346-50

PMID: 23177787 · PMCID: PMC3535830 · DOI:10.1016/j.bmcl.2012.10.073

Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=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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MeSH Terms (16)

Allosteric Regulation Amides Animals Brain Cholinergic Agents Disease Models, Animal Drug Evaluation, Preclinical Half-Life Humans Protein Binding Pyridines Rats Receptor, Muscarinic M4 Schizophrenia Structure-Activity Relationship Thiophenes

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