美国加州大学David E. Olson团队的一项最新研究揭示了具有治疗潜力的非致幻迷幻剂类似物。这一研究成果在线发表在2020年12月9日出版的国际学术期刊《自然》上。
研究人员首先运用功能导向的合成原理确定了伊博加因潜在药效基团的关键结构，然后利用这些信息设计了taberanthalog，这是一种水溶性、非致幻、无毒的伊博加因类似物，其可以通过一步合成。在啮齿动物中，研究人员发现taberanthalog可改善神经结构的可塑性，减少寻求酒精和海洛因的行为，并产生类似抗抑郁药的功效。这项工作表明，通过精细的化学设计可改良迷幻类化合物，从而产生具有治疗潜力的更安全、无致幻性变体。
研究人员表示，致幻生物碱伊博加因对人和动物均具有抗成瘾性。与大多数用于治疗药物滥用的药物不同，有报告指出，伊博加因具有治疗多种药物成瘾的潜力，包括鸦片、酒精和精神兴奋剂。与其他致幻化合物一样，伊博加因可发挥持久性功能，这归因于其具有通过激活神经营养因子信号传导改变成瘾相关神经回路的能力。但是，一些安全性问题阻碍了依博加因在临床上的应用，包括其毒性、致幻作用和可能诱发心律不齐。
附：英文原文
Title: A non-hallucinogenic psychedelic analogue with therapeutic potential
Author: Lindsay P. Cameron, Robert J. Tombari, Ju Lu, Alexander J. Pell, Zefan Q. Hurley, Yann Ehinger, Maxemiliano V. Vargas, Matthew N. McCarroll, Jack C. Taylor, Douglas Myers-Turnbull, Taohui Liu, Bianca Yaghoobi, Lauren J. Laskowski, Emilie I. Anderson, Guoliang Zhang, Jayashri Viswanathan, Brandon M. Brown, Michelle Tjia, Lee E. Dunlap, Zachary T. Rabow, Oliver Fiehn, Heike Wulff, John D. McCorvy, Pamela J. Lein, David Kokel, Dorit Ron, Jamie Peters, Yi Zuo, David E. Olson
Issue&Volume: 2020-12-09
Abstract: The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine—like those of other psychedelic compounds—are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog—a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.
DOI: 10.1038/s41586-020-3008-z
Source: https://www.nature.com/articles/s41586-020-3008-z
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
