AbstractMitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.
摘要:Mitragynine(MG)是致幻植物“荷乐蒂”中最丰富的生物碱成分,根据众多个人经验报告,显示出在自我药物治疗疼痛综合征、抑郁、焦虑和物质使用障碍方面的有效性。我们已经开发了一种合成方法,用于选择性功能化MG骨架的未开发的C11位置(在吲哚编号中为C6位置),通过使用吲哚-乙二醇加合物和随后的铱催化硼化反应。通过这项工作,我们发现C11代表了微调阿片受体信号效力的关键位置。 7-羟基荷乐蒂(7OH),作为与丁丙诺啡具有低效力的母体化合物,通过在这个位置引入氟取代基(11-F-7OH)转化为甚至更低效力的激动剂,这在小鼠和人类μ阿片受体(mMOR/hMOR)的体外实验以及小鼠镇痛实验中得到证实。低效力阿片激动剂对于作为产生更安全的阿片类药物候选药物具有高度兴趣,以减轻不良反应。