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
  • 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.
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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