Synthesis and Pharmacology of a Novel μ–δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template

Abstract

In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (μOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named <b>MP135</b> that exhibits high G-protein activity at μ-δ heteromers compared to the homomeric δOR or μOR and low β-arrestin2 recruitment activity at all three. Furthermore, <b>MP135</b> exhibits distinct signaling profile, as compared to the previously identified agonist targeting μ-δ heteromers, CYM51010. Pharmacological characterization of <b>MP135</b> supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. <i>In vivo</i> characterization reveals that <b>MP135</b> maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of <b>MP135</b> is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids.