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

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.