Tetrahydroquinoline-Based Negative Allosteric Modulators of the µ-Opioid Receptor as Potential Therapeutics for Opioid Use Disorder

Ali Berry

Research Mentor: Mengchu Li
Mentor Department: Pharmacology, Medicine
Author(s): Ali Berry, Jason Rech, John Traynor, Mengchu Li
Session: Session 1 (9:00 AM – 9:50 AM)
Presentation Type: Poster 57

Abstract

Trends in synthetic opioids abuse have displayed a drastic increase over recent years, and are most often used to induce analgesia and euphoria, while subsequently depressing respiratory rate. Opioid agonists such as fentanyl and morphine target the Mu-Opioid Receptor, which can be selectively modulated for the less favorable binding of such agonists. We hypothesize that Negative Allosteric Modulators (NAMs) may represent a promising strategy in reducing affinity of receptor-agonist interactions. After binding to the receptor in a region other than the orthosteric site, NAMs induce conformational changes, ultimately reducing the affinity of the agonist for the receptor. This decreases receptor activation, thus, less euphoria and respiratory depression are expected to occur in vivo models. The goal of this project is to explore the relationship between structural features and NAM potency in reducing MOR activation . To quantify the data, an in vitro GTPyS biochemical assay has been employed, in which DAMGO served as the control agonist, activating the MOR and exchanging the GDP for a GTP indicating the active state. In radio-labeling the GTP with 35S, we can quantify the amount of activity by the receptor in counts, as GTPyS is not as susceptible to the inherent GTPase activity of degradation With the receptor preserved in the “on state”, DAMGO’s activity and the reduction of its activity can be reliably measured in the presence of various concentrations of NAMs. The potency of each NAM will be determined by the concentration-response curve, indicated by IC50, the concentration of a NAM to reduce 50% DAMGO’s activity. Hence the more potent NAM, the lower the value of IC50 it will present. Following a set of systematic GTPyS assays, we will summarize the structure-activity relationship for a group of tetrahydroquinoline NAMs to direct future NAM structure design, and evaluate the most potent NAM in in vivo models.