Sophie Mensch
Research Mentor(s): Mengchu Li
Mentor Department: Pharmacology
Authors: Sophie Mensch, Jason Rech, Mengchu Li, John Traynor
Session: Session 7 (4:00pm – 4: 50pm)
Presentation Type: Oral
Abstract
The µ-opioid receptor (MOR), a member of the opioid receptor family, is the most pharmacologically targeted G-Protein Coupled Receptor for its pain management properties. However, despite contributing to pain relief, these opioid agonists have an abuse liability and often result in opioid use disorder (OUD). The American Medical Association estimates that 3-19% of individuals who take prescription pain medications develop OUD. While there are three FDA-approved OUD treatments, which target MOR, they precipitate severe withdrawal symptoms by binding either directly or partially to MOR’s orthosteric site (i.e. where opioid agonists bind), leading to low patient compliance. In response to the growing need for better OUD treatments, we are exploring a new mechanism: negative allosteric modulation. Unlike competitive mechanisms that bind directly to the orthosteric site (i.e. where opioid agonists and current treatments bind), negative allosteric modulators (NAMs) bind to a different site on MOR, allowing them to diminish activation of MOR by opioid agonists without directly competing for binding. This distinction is crucial, as it may allow MOR-NAMs to lessen withdrawal and prevent relapse while avoiding the abuse liability associated with current treatments. Due to these features of NAMs, we hypothesized that MOR-NAMs would offer a safer and more effective alternative for treating OUD. In the presented study, we identified compound 698 out of 15 novel MOR-NAM compounds as a promising candidate due to its high potency. After verifying its in vivo activity, we evaluated its withdrawal adverse effects in opioid-dependent mice. Compared to the standard treatment, naltrexone (NTX), we observed significantly less withdrawal in mice for compound 698, making it a potential candidate for clinical trial.
