Project Summary
Opioid use disorder (OUD) has grown to epidemic proportions over the past few decades, affecting millions
of Americans and contributing to tens of thousands of deaths each year. While medication is a cornerstone
for the treatment of OUD, current therapeutics act upon the mu opioid receptor (MOR) itself. MOR agonists
have a high risk of misuse and so their administration must be tightly regulated, while MOR antagonists
necessitate a supervised withdrawal period before the beginning of treatment. These requirements create
significant barriers to access for people with OUD who seek treatment. An alternative strategy for the
treatment of OUD is to target receptors other than MOR which mediate addiction. One such target is the
serotonin 2C (5-HT2C) receptor, which exerts tonic inhibition over mesolimbic dopaminergic signaling, the
pathway underlying the brain's reward response to stimuli such as drugs of abuse. Preclinical data has
validated 5-HT2C agonism as an effective means for treating addiction to cocaine, alcohol, and nicotine.
Though less extensively investigated, recent preclinical studies have supported the efficacy of 5-HT2C
agonism against opioid addiction as well. In the course of our studies of metabolites of yohimbine natural
products, we have designed and synthesized a lead compound exhibiting agonism of 5-HT2C. The
objective of my proposal is the further development of a potent, biased, and selective small molecule 5-
HT2C agonist followed by efficacy studies in animal models for opioid addiction. Synthesis of analogs of our
lead compound will be guided by computational molecular docking and informed by in vitro functional
assays for potency, bias, and selectivity, and top analogs will be advanced into pharmacokinetic and
toxicity testing. Selected analogs will then be advanced into in vivo efficacy studies, using a drug-induced
Conditioned Place Preference assay in mice. This research training plan encompasses medicinal
chemistry, organic synthesis, computational modeling, chemical biology, neuroscience, and in vivo assay
techniques. It will be carried out as part of a collaborative effort between the Northwestern University
Department of Chemistry and the Feinberg School of Medicine Translational Neuropharmacology Program,
with further support from outside collaborators.
