Lori Ourlian
Research Mentor: Mengchu Li
Mentor Department: Pharmacology, Medicine
Author(s): Lori Ourlian, Jason Rech, John Traynor, Mengchu Li
Session: Session 5 (2:00 PM – 2:50 PM)
Presentation Type: Poster 22
Abstract
The opioid epidemic remains a major public health crisis in the United States, with an estimated 6.1 million individuals aged 12 or older affected by opioid use disorder (OUD) in 2022. Opioid agonists such as oxycodone, fentanyl, and nitazenes exert their effects through activation of the µ-opioid receptor (MOR), a G-protein-coupled receptor. While MOR activation provides effective analgesia, it is also associated with significant adverse effects, including addiction and respiratory depression. Although current treatments (naltrexone, buprenorphine and methadone) improve clinical outcomes, severe withdrawal stops patients to receive treatments and the relapse rates still remain high (65–70%), highlighting the need for improved therapeutic strategies. Negative allosteric modulators (NAMs) offer a promising approach. NAMs bind to a site distinct from the orthosteric ligand-binding site and modulate activity without totally blocking the receptor. As a result, NAMs inhibit opioid signaling in a non-competitive manner, potentially reducing abuse liability, minimizing withdrawal severity, and lowering the risk of relapse. In this study, 17 NAM compounds of two different chemical scaffolds were evaluated for their effects on DAMGO (an MOR agonist)-induced MOR activation using the ³5S-GTP?S binding assay. This assay measures G-protein activation by quantifying the binding of radioactive ³5S-GTP?S to active G-proteins. Membrane preparations were treated with varying concentrations of NAMs in the presence of DAMGO, and changes in receptor signaling were assessed and potency of each NAM was calculated. Structure-activity (potency) relationships were then analyzed for two scaffolds respectively. These findings will be used in future NAM structure design and identification of a potential drug candidate.
