Discovery of 6α-Thiazolylcarboxamidonaltrexamine\nDerivative (NTZ) as a Potent and Central Nervous System Penetrant\nOpioid Receptor Modulator with Drug-like Properties for Potential\nTreatment of Opioid Use Disorder

The development of highly potent and selective μ\nopioid receptor\n(MOR) modulators with favorable drug-like properties has always been\na focus in the opioid domain. Our previous efforts led to the discovery\nof a lead compound designated as NAT, a potent centrally acting MOR\nmodulator. However, the fact that NAT precipitated considerable withdrawal\neffects at higher doses largely impaired its further development.\nIn the light of the concept of activity cliff and CNS multiparameter\noptimization algorithm, a nitrogen atom was incorporated into the\nthiophene ring of NAT, aiming to preserve desirable pharmacological\nactivities and CNS permeability while alleviating withdrawal symptoms.\nAmong all 16 new analogs, compound <b>6</b> (NTZ) exhibited\nimproved opioid receptor selectivity, enhanced <i>in vivo</i> antagonistic effect, and overall fewer withdrawal symptoms compared\nto NAT. Further assessment of several key drug-like properties suggested\na favorable ADMET profile of NTZ. Taken together, NTZ shows promise\nas a potential lead to treat opioid use disorder.