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Short-acting μ-opioid receptor (MOR) agonists have long been used for the treatment of severe, breakthrough pain. However, selective MOR agonists including fentanyl and morphine derivatives are limited clinically due to high risks of dependence, tolerance, and respiratory depression. We recently reported the development of a long-acting, bifunctional MOR agonist/δ-opioid receptor (DOR) antagonist analgesic devoid of tolerance or dependence in mice (AAH8, henceforth referred to as 2B). To address the need for short-acting treatments for breakthrough pain, we present a series of novel, short-acting, high-potency MOR agonist/DOR antagonist ligands with antinociceptive activity in vivo. In this study, we utilized a two-dimensional structure-activity relationship matrix to identify pharmacological trends attributable to combinations of two key pharmacophore elements within the chemotype. This work enhances our ability to modulate efficacy at MOR and DOR, accessing a variety of bifunctional profiles while maintaining high affinity and potency at both receptors.

Dual Pharmacophores Explored via Structure–Activity Relationship (SAR) Matrix: Insights into Potent, Bifunctional Opioid Ligand Design