Sophie Mensch
Pronouns: she/her
Research Mentor(s): Mengchu Li
Research Mentor School/College/Department: Pharmacology / Medicine
Program:
Authors: Sophie Mensch, Brennan Watch, Jesse Duque, Jason Rech, Mengchu Li, John Traynor
Session: Session 6: 3:40 pm – 4:30 pm
Poster: 2
Abstract
According to the DSM 5-TR, Opioid Use Disorder (OUD) is “a problematic pattern of opioid use leading to problems or distress.” Opioid agonists, chemicals that activate opioid receptors such as morphine and fentanyl, contribute to pain relief, but they also cause constipation, euphoria (which is closely linked to abuse liability), and both physical and psychological dependence. Administering buprenorphine and/or naltrexone (NTX), an orthosteric partial agonist and antagonist respectively, is the current treatment. These drugs, however, can precipitate severe withdrawal symptoms, resulting in low patient compliance. More notably, these treatments are unsuccessful in preventing patients from relapsing (50% relapse rate in OUD patients). Looking at the limitations of medications currently on the market, there is clearly a need for an improved OUD treatment. Therefore, we are using a new mechanism—negative allosteric modulation—to discover and design better drug candidates for OUD. Negative Allosteric Modulators (NAMs) bind to a different site than the orthosteric site (i.e. where morphine and all three aforementioned drugs bind) and as a result can effectively diminish the activation from agonists in a non-surmountable manner. Because NAMs act at a different site, it is promising that NAMs will precipitate less withdrawal and prevent relapse. In the present study, ten novel compounds were tested by conducting a cAMP-Glo assay to measure their potency. The high potency NAMs are of considerable interest and will be tested in mice to verify their in vivo activity. In addition, combined with previous studies, we have drawn several structure-activity relationships to help design better NAMs.
