Structural Analysis of Delta Opioid Receptor Ligands for Chronic Pain Therapeutics

Abstract ID 95191 Poster Board 084 Chronic pain is highly prevalent and is one of the most common reasons adults seek medical attention. Unfortunately, current therapeutics to treat this type of pain are limited due to low efficacy and/or high side effect profile. Delta opioid receptor (DOR) agonists have been found to be particularly effective at treating chronic pain and have anxiolytic and anti-depressant effects which are commonly comorbid with chronic pain. However, DOR agonists exhibit negative side effects like seizures and tolerance. To develop safe and effective DOR agonists, we need to understand how they bind and signal. We have used cryo-electron microscopy (cryoEM) to solve DOR-Gi1 structures of pharmacologically distinct agonists, including an endogenous peptide, a seizure-causing ligand, a seizure-free ligand which entered Phase 2 clinical trials, an antagonist, and a structure with a positive allosteric modulator. We have also solved the DOR-Gi1 structure of a newly developed DOR partial agonist which is effective at treating different types of pain in mice, including chronic pain, and has a limited side effect profile. Comparing cryoEM structures of DOR agonists with different signaling and behavioral profiles can guide the development of next-generation DOR agonists to treat chronic pain. This research was supported by the PhRMA foundation and NIH grant R01DA057790.