A non-hallucinogenic psychedelic analogue with therapeutic potential.
A non-hallucinogenic psychedelic analogue with therapeutic potential.
复制标题
DOI：
10.1038/s41586-020-3008-z
复制
发表时间：
2021-01
期刊：
影响因子：
64.8
通讯作者：
Olson DE
中科院分区：
文献类型：
--
作者：
Cameron LP;Tombari RJ;Lu J;Pell AJ;Hurley ZQ;Ehinger Y;Vargas MV;McCarroll MN;Taylor JC;Myers-Turnbull D;Liu T;Yaghoobi B;Laskowski LJ;Anderson EI;Zhang G;Viswanathan J;Brown BM;Tjia M;Dunlap LE;Rabow ZT;Fiehn O;Wulff H;McCorvy JD;Lein PJ;Kokel D;Ron D;Peters J;Zuo Y;Olson DE
迷幻生物碱伊博格碱对人类和动物都有抗上瘾的特性。与大多数物质使用障碍（SUD）药物不同，坊间报道表明，伊博加因具有治疗对各种物质成瘾的患者的潜力，包括阿片类药物、酒精和精神兴奋剂。像其他致幻剂一样，它的治疗效果是持久的，这归因于它能够通过激活神经营养因子信号来改变与成瘾相关的神经回路。然而，一些安全性问题阻碍了伊博加因的临床发展，包括其毒性、致幻觉潜力和诱发心律失常的倾向。在这里，我们应用功能导向合成（FOS）的原理来确定其潜在治疗药效团的关键结构元素，使我们能够设计出他伯南他罗（TBG）——一种水溶性、无致幻剂、无毒的伊博格碱类似物，可以在一个步骤中制备。在啮齿类动物中，TBG促进了结构神经可塑性，减少了酒精和海洛因寻求行为，并产生了类似抗抑郁的效果。这项工作表明，通过仔细的化学设计，有可能修改一种迷幻化合物，以产生一种更安全、非致幻的具有治疗潜力的变体。
The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals. Unlike most substance use disorder (SUD) medications, anecdotal reports suggest that ibogaine possesses the potential to treat patients addicted to a variety of substances including opiates, alcohol, and psychostimulants. Like other psychedelic compounds, its therapeutic effects are long-lasting, which has been attributed to its ability to modify addiction-related neural circuitry through activation of neurotrophic factor signaling. However, several safety concerns have hindered the clinical development of ibogaine including its toxicity, hallucinogenic potential, and proclivity for inducing cardiac arrhythmias. Here, we apply the principles of function-oriented synthesis (FOS) to identify the key structural elements of its potential therapeutic pharmacophore, enabling us to engineer tabernanthalog (TBG)—a water soluble, non-hallucinogenic, non-toxic analog of ibogaine that can be prepared in a single step. TBG promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects in rodents. This work demonstrates that through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant with therapeutic potential.
登录
查看更多内容
影响因子：
2.9
作者：
GLICK, SD;KUEHNE, ME;CARLSON, JN
通讯作者：
CARLSON, JN
DOI：
10.3390/molecules20022208
发表时间：
2015-01-29
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Koenig X;Hilber K
通讯作者：
Hilber K
影响因子：
8.8
作者：
Ly C;Greb AC;Cameron LP;Wong JM;Barragan EV;Wilson PC;Burbach KF;Soltanzadeh Zarandi S;Sood A;Paddy MR;Duim WC;Dennis MY;McAllister AK;Ori-McKenney KM;Gray JA;Olson DE
通讯作者：
Olson DE
影响因子：
3.8
作者：
Dach, Katharina;Yaghoobi, Bianca;Lein, Pamela J.
通讯作者：
Lein, Pamela J.
影响因子：
3.4
作者：
Carnicella, Sebastien;He, Dao-Yao;Ron, Dorit
通讯作者：
Ron, Dorit