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

Madeline F Long; Rory A Capstick; Paul K Spearing; Julie L Engers; Alison R Gregro; Sean R Bollinger; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Craig W Lindsley; Darren W Engers; Kayla J Temple

doi:10.1016/j.bmcl.2021.128416

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. Epub 2021 Oct 26.

Authors

Madeline F Long¹, Rory A Capstick¹, Paul K Spearing¹, Julie L Engers¹, Alison R Gregro¹, Sean R Bollinger¹, Sichen Chang¹, Vincent B Luscombe¹, Alice L Rodriguez¹, Hyekyung P Cho¹, Colleen M Niswender², Thomas M Bridges¹, P Jeffrey Conn², Craig W Lindsley³, Darren W Engers¹, Kayla J Temple⁴

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: kayla.temple@vanderbilt.edu.

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Muscarinic M4 / antagonists & inhibitors*
Receptor, Muscarinic M4 / metabolism
Structure-Activity Relationship

Substances

Pyrimidines
Receptor, Muscarinic M4
pyrimidine

Abstract

Publication types

MeSH terms

Substances

Grants and funding