Project Summary/Abstract Opioids acting at the mu opioid receptor (MOR) remain the gold standard for treatment of moderate to severe pain relief, but their use is limited by serious side effects, particularly abuse liability. The opioid epidemic has grown steadily in the past three decades, resulting in 137 deaths per day. In this program, we will test modifications of the core pharmacophore of an endomorphin analog that has been shown to provide pain relief comparable to morphine while exhibiting reduction of several side effects, including abuse liability. A series of glycosylated analogs of endomorphin, designed to enhance blood-brain-barrier penetration, will be tested. Preliminary tests indicate highly effective acute antinociception/pain relief for 2 of these compounds. We will identify 3 candidate compounds and assess them for low abuse liability in rodent models that correlate with human abuse liability. We will then test for reduction of tolerance and respiratory depression relative to currently used opioids, and effective relief of 3 forms of pain ranging from moderate to chronic duration. Pharmacokinetic profiles will enable planning of human studies. The goal of this project is to show proof-of-concept that these novel endomorphin analogs can provide effective treatment of pain without rewarding properties and other key adverse effects. Successful outcomes of this project will support development of these compounds for clinical use as novel treatments for pain and potentially for opioid use disorder.