Development of Tetrahydroquinoline-Based Inhibitors for Chronic Pain

• Published in: ACS chemical neuroscience Vol. 15; no. 20; pp. 3704 - 3712
• Main Authors: Patel, Ketul V., Gadotti, Vinicius M., Garcia-Caballero, Agustin, Antunes, Flavia T. T., Ali, Md Yousof, Zamponi, Gerald W., Derksen, Darren J.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-10-2024
• Subjects: chronic pain; T-type; USP5; tetrahydroquinoline; Cav3.2; small molecules
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.4c00316

Chronic pain affects a substantial portion of the population, posing a significant health challenge. Current treatments often come with limitations and side effects, necessitating novel therapeutic approaches. Our study focuses on disrupting the Cav3.2-USP5 interaction as a strategy for chronic pain management. Through structure–activity relationship studies of a tetrahydroquinoline (THQ) scaffold, we identified a family of lead molecules that demonstrated potent inhibition of the Cav3.2-USP5 interaction. In vitro pharmacokinetic assessments and in vivo studies support the efficacy and drug-like properties of the lead compounds in mouse models of acute and chronic pain. Dependence on the Cav3.2 channels was validated in Cav3.2 null mice, consistent with the proposed mode of action of these small molecules. These findings provide a novel chronic pain treatment strategy, highlighting the potential of these small molecules for further development.