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 journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)346-350
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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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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