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

Aaron T Garrison; Douglas L Orsi; Rory A Capstick; David Whomble; Jinming Li; Trever R Carter; Andrew S Felts; Paige N Vinson; Alice L Rodriguez; Allie Han; Krishma Hajari; Hyekyung P Cho; Laura B Teal; Madeline G Ragland; Masoud Ghamari-Langroudi; Michael Bubser; Sichen Chang; Nathalie C Schnetz-Boutaud; Olivier Boutaud; Anna L Blobaum; Daniel J Foster; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Carrie K Jones; Changho Han

doi:10.1021/acs.jmedchem.2c00192

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. Epub 2022 Apr 13.

Authors

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.

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 M_1-4) 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.

Publication types

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

MeSH terms

Animals
Dopaminergic Neurons
Male
Opioid-Related Disorders*
Rats
Rats, Sprague-Dawley
Receptor, Muscarinic M1
Receptor, Muscarinic M5*
Receptors, Muscarinic

Substances

Receptor, Muscarinic M1
Receptor, Muscarinic M5
Receptors, Muscarinic

Grants and funding

S10 OD021734/OD/NIH HHS/United States