2. Academic Validation
  3. Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2

Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2

  • Bioorg Med Chem Lett. 2021 Dec 1:53:128416. doi: 10.1016/j.bmcl.2021.128416.
Madeline F Long 1,  Rory A Capstick 1,  Paul K Spearing 1,  Julie L Engers 1,  Alison R Gregro 1,  Sean R Bollinger 1,  Sichen Chang 1,  Vincent B Luscombe 1,  Alice L Rodriguez 1,  Hyekyung P Cho 1,  Colleen M Niswender 2,  Thomas M Bridges 1,  P Jeffrey Conn 2,  Craig W Lindsley 3,  Darren W Engers 1,  Kayla J Temple 4
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 2 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 34710625 DOI: 10.1016/j.bmcl.2021.128416
Abstract

This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.

Keywords

M(4); Muscarinic acetylcholine receptor; Positive Allosteric modulator (PAM); Structure Activity Relationship (SAR).

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