Landscaping the Nitazene Scaffold to Identify Novel Mu-Opioid Receptor Modulators: From Molecular Design and Chemical...

The surge in ultrapotent synthetic opioids has intensified the need for new chemical strategies for modulating the mu-opioid receptor (MOR). In this study, nitazene scaffold, a chemically distinct and underexplored chemotype, was utilized as an underexplored framework for MOR modulation. Structure-activity relationship studies were conducted through modifications at three key positions of the nitazene core and evaluated for MOR binding, in vitro functional, and in vivo behavioral activities. Among them, compound 26 significantly blocked the effects of synthetic opioids, including fentanyl and etonitazene. It also demonstrated affinity and selectivity for MOR and exhibited favorable metabolic stability and CNS permeability. Molecular modeling studies provided structural insights into potential binding modes of these ligands. This work expands the chemical space for opioid receptor ligands and provides a proof-of-concept that the nitazene core is chemically tunable for MOR functional modulation, highlighting nitazenes as a promising platform for future therapeutic exploration.