美国国家药物滥用研究所Michael Michaelides团队研制了一种副作用极小的μ-阿片受体超级激动剂镇痛药。相关论文于2026年4月1日发表在《自然》杂志上。

在这里，研究团队确定了一种新的MOR激动剂，具有超强的内在功效和独特的药理学特征，在啮齿类动物中产生有效的镇痛作用，副作用最小。N-去乙基氟硝基（DFNZ）是由一类合成的苯并咪唑类阿片类药物硝氮烯衍生而来。DFNZ具有脑外显率受损，独特的时空MOR细胞信号传导谱，并且对MOR- GAL1受体（GAL1）异聚体的功效降低。重复暴露后，DFNZ不会引起呼吸抑制、耐受性或MOR下调。与其他MOR激动剂相比，DFNZ对伏隔核多巴胺神经传递的影响有限，在给药过程中的强化作用较弱。这些结果提供了关于MOR和硝氮烯药理学的新见解，对疼痛和成瘾治疗具有重要意义，并挑战了高效MOR激动剂不能构成安全有效治疗剂的普遍教条。

研究人员表示，开发安全有效的止痛药是人类健康面临的一项持续挑战。μ-阿片受体激动剂（MOR）是必不可少的镇痛药物，但其高内在疗效也会引起不良副作用，包括呼吸抑制、便秘、耐受性、依赖性、戒断和成瘾。传统上限制不良反应的策略包括开发具有低内在功效或优先激活G蛋白信号而不是β-抑制素信号的MOR激动剂。

附：英文原文

Title: A μ-opioid receptor superagonist analgesic with minimal adverse effects

Author: Gomez, Juan L., Ventriglia, Emilya N., Frangos, Zachary J., Sulima, Agnieszka, Robertson, Michael J., Sacco, Michael D., Budinich, Reece C., Giosan, Ilinca M., Xie, Tongzhen, Solis, Oscar, Tischer, Anna E., Bossert, Jennifer M., Caldwell, Kiera E., Bonbrest, Hannah, Essmann, Amelie, Garon-Poca, Zelai M., Choi, Shinbe, Noya, Michael R., Limiac, Feonil, Arce, Ali, Glatfelter, Grant C., Robinson, Margaret, Chen, Li, Mullarkey, Angelina A., Brademan, Dain R., Enten, Garrett, Dunne, William, Quiroz, Csar, Schoenborn, Ingrid, Lee, Chae Bin, Rais, Rana, Holt, Daniel P., Dannals, Robert F., Shi, Lei, Httenhain, Ruth, Ferr, Sergi, Kiyatkin, Eugene, Bonaventura, Jordi, Shaham, Yavin, Zachariou, Venetia, Baumann, Michael H., Skiniotis, Georgios, Rice, Kenner C., Michaelides, Michael

Issue&Volume: 2026-04-01

Abstract: Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the μ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction1,2,3,4,5,6,7. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling8. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR–galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.

DOI: 10.1038/s41586-026-10299-9

Source: https://www.nature.com/articles/s41586-026-10299-9