Hannah Stewart
Pronouns: she/her/hers
Research Mentor(s): Mengchu Li
Research Mentor School/College/Department: Pharmacology / Medicine
Program:
Authors: Hannah Stewart, Sherrice Zhang, Andrew Alt, Andrew White, Mengchu Li, John Traynor
Session: Session 4 1:40-3:30 p.m. Hussey Room
Poster:
Abstract
The co-occurrence of depression and chronic pain affects an estimated 12 million adults in the U.S. The d-opioid receptor (DOR) is a member of the opioid receptor family and is involved in both mood regulation and pain. Researched DOR orthosteric agonists have analgesic and antidepressant effects without the abuse liability that is intrinsically elicited by the ยต-opioid receptor (MOR) agonists, such as fentanyl and morphine. Thus, DOR remains a valuable target for drug design to treat both depression and pain. However, the over-activation of DOR by orthosteric agonists can induce convulsive activity, so orthosteric activation may not be the best avenue to explore in DOR drug design. Alternatively, the positive allosteric modulation of DOR can be exploited as a safer avenue due to ceiling effects. Also, positive allosteric modulators (PAMs) activate the receptor only when in the presence of an orthosteric agonist and reduce the risk of off-target effects and tolerance. Therefore, we performed a structure-activity relationship study of a known DOR PAM, BMS986187, to identify potent DOR PAMs and assist future drug design. In the presented study, we designed and synthesized 16 novel analogs and tested them for their in vitro potency using the beta-arrestin recruitment assay. BMS986187 has a potency of 75 nM, and in our study, we have identified two compounds with 2-fold higher potency and other useful structure-activity relationships. In the future, compounds will be tested for selectivity and in vivo activity.
