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

  • Bioorg Med Chem Lett. 2013 Jan 1;23(1):346-50. doi: 10.1016/j.bmcl.2012.10.073.
Uyen Le  1 ,  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
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
PMID: 23177787 DOI: 10.1016/j.bmcl.2012.10.073
Abstract

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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