2. Academic Validation
  3. Development of VU6019650: A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M5 Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder

Development of VU6019650: A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M5 Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder

  • J Med Chem. 2022 Apr 28;65(8):6273-6286. doi: 10.1021/acs.jmedchem.2c00192.
Aaron T Garrison 1 2,  Douglas L Orsi 1 2,  Rory A Capstick 1 2,  David Whomble 1 2,  Jinming Li 1 2,  Trever R Carter 1 2,  Andrew S Felts 1 2,  Paige N Vinson 1 2,  Alice L Rodriguez 1 2,  Allie Han 1 2,  Krishma Hajari 1 2,  Hyekyung P Cho 1 2,  Laura B Teal 1 2,  Madeline G Ragland 1 2,  Masoud Ghamari-Langroudi 1 2,  Michael Bubser 1 2,  Sichen Chang 1 2,  Nathalie C Schnetz-Boutaud 1 2,  Olivier Boutaud 1 2,  Anna L Blobaum 1 2,  Daniel J Foster 1 2 3,  Colleen M Niswender 1 2 3,  P Jeffrey Conn 1 2 3,  Craig W Lindsley 1 2 4 5,  Carrie K Jones 1 2,  Changho Han 1 2
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.
  • 3 Vanderbilt Kennedy Center, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.
  • 4 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 35417155 DOI: 10.1021/acs.jmedchem.2c00192
Abstract

The Muscarinic Acetylcholine Receptor (mAChR) subtype 5 (M5) represents a novel potential target for the treatment of multiple addictive disorders, including opioid use disorder. Through chemical optimization of several functional high-throughput screening hits, VU6019650 (27b) was identified as a novel M5 orthosteric antagonist with high potency (human M5 IC50 = 36 nM), M5 subtype selectivity (>100-fold selectivity against human M1-4) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, 27b blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover, 27b also inhibited oxycodone self-administration in male Sprague-Dawley rats within a dose range that did not impair general motor output.

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