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

The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound 6 (NTZ) exhibited improved opioid receptor selectivity, enhanced in vivo antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.

开发具有优良类药性质的强效、高选择性μ阿片受体（μ opioid receptor, MOR）调节剂，始终是阿片类药物研究领域的核心攻关方向。本团队前期研究发现了一款命名为NAT的先导化合物，其为强效中枢作用型MOR调节剂。但NAT在较高剂量下可诱发显著的戒断反应，这极大限制了其后续开发进展。基于活性悬崖（activity cliff）与中枢神经系统（central nervous system, CNS）多参数优化算法的研发理念，研究人员在NAT的噻吩环结构中引入了一个氮原子，以期在保留理想药理活性与CNS穿透性的同时，减轻戒断症状。在全部16种新合成的类似物中，化合物6（NTZ）相较NAT展现出更优的阿片受体选择性、更强的体内拮抗活性，且整体戒断反应发生率更低。后续对多项关键类药性质的评估结果显示，NTZ具备优良的ADMET（Absorption, Distribution, Metabolism, Excretion, Toxicity）特性谱。综上，NTZ有望成为治疗阿片类使用障碍的潜在先导化合物。