Li Mengchu, Gan Xinmin, Liu Kun, Walajapet Rajeswaran, Stanczyk M Alex, Stewart Hannah C, Rech Jason C, White Andrew D, Traynor John R
Edward F Domino Research Center, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS Chem Neurosci. 2025 Jan 1;16(1):16-29. doi: 10.1021/acschemneuro.4c00541. Epub 2024 Dec 11.
Positive allosteric modulation of the mu-opioid receptor is a promising strategy to address the ever-growing problem of acute and chronic pain management. Positive allosteric modulators (PAMs) of the mu-opioid receptor could be employed to enhance the efficacy of endogenous opioid peptides to a degree that provides pain relief without the need for traditional opioid drugs. Alternatively, PAMs might be used to enhance the action of opioid drugs and so provide an opioid-sparing effect, allowing for the use of lower doses of opioid agonists and potentially decreasing associated side effects. BMS-986122 (2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl)-sulfonyl]-thiazolidine) has been previously identified as a PAM of the mu-opioid receptor. In the present work, we have designed and synthesized 33 analogs of BMS-986122 to explore the structure-activity relationships of this scaffold and confirm its allosteric mechanism of action. Among several newly identified modulators, the most promising compound () had improved activity to increase the in vitro potency of the standard mu-opioid agonist DAMGO and showed in vivo activity in mice to enhance the antinociceptive action of morphine.
μ-阿片受体的正变构调节是解决日益严重的急慢性疼痛管理问题的一种有前景的策略。μ-阿片受体的正变构调节剂（PAMs）可用于增强内源性阿片肽的功效，达到在无需传统阿片类药物的情况下缓解疼痛的程度。或者，PAMs可用于增强阿片类药物的作用，从而产生阿片类药物节省效应，允许使用更低剂量的阿片类激动剂，并可能减少相关副作用。BMS-986122（2-(3-溴-4-甲氧基苯基)-3-[(4-氯苯基)-磺酰基]-噻唑烷）先前已被鉴定为μ-阿片受体的PAM。在本研究中，我们设计并合成了33种BMS-986122的类似物，以探索该骨架的构效关系并确认其变构作用机制。在几种新鉴定的调节剂中，最有前景的化合物（）提高了增加标准μ-阿片激动剂DAMGO体外效力的活性，并在小鼠体内显示出增强吗啡镇痛作用的活性。
