Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Campus Heymans, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 18 Kremlyovskaya Str., 420008 Kazan, Russian Federation.
ACS Chem Neurosci. 2021 May 5;12(9):1667-1673. doi: 10.1021/acschemneuro.1c00124. Epub 2021 Apr 28.
Serotonergic psychedelics, substances exerting their pharmacological action through activation of the serotonin 2A receptor (5-HTR), have continuously comprised a substantial fraction of the over 1000 reported New Psychoactive Substances (NPS) so far. Within this category, -benzyl derived phenethylamines, such as NBOMes and NBFs, have shown to be of particular relevance. As these substances remain incompletely characterized, this study aimed at synthesizing positional isomers of 25H-NBF, with two methoxy groups placed on different positions of the phenyl group of the phenethylamine moiety. These isomers were then functionally characterized in an bioassay monitoring the recruitment of β-arrestin 2 to the 5-HTR through luminescent readout via the NanoBiT technology. The obtained results provide insight into the optimal substitution pattern of the phenyl group of the phenethylamine moiety of -benzyl derived substances, a feature so far mostly explored in the phenethylamines underived at the -position. In the employed bioassay, the most potent substances were 24H-NBF (EC value of 158 nM), 26H-NBF (397 nM), and 25H-NBF (448 nM), with 23H-NBF, 35H-NBF, and 34H-NBF yielding μM EC values. A similar ranking was obtained for the compounds' efficacy: taking as a reference LSD (lysergic acid diethylamide), 24H-, 26H-, and 25H-NBF had an efficacy of 106-107%, followed by 23H-NBF (96.1%), 34H-NBF (75.2%), and 35H-NBF (58.9%). The stronger activity of 24H-, 25H-, and 26H-NBF emphasizes the important role of the methoxy group at position 2 of the phenethylamine moiety for the functionality of NBF substances.
血清素能致幻剂，通过激活血清素 2A 受体（5-HTR）发挥其药理作用的物质，一直占迄今为止报告的 1000 多种新精神活性物质（NPS）的很大一部分。在这个类别中，-苄基衍生的苯乙胺，如 NBOMes 和 NBFs，已被证明具有特别重要的意义。由于这些物质仍未被完全描述，本研究旨在合成 25H-NBF 的位置异构体，即在苯乙胺部分的苯环上的两个甲氧基放在不同的位置。然后，通过使用纳米生物发光技术通过发光读出监测β-arrestin 2 与 5-HTR 的募集来对这些异构体进行功能表征。获得的结果深入了解了 -苄基衍生物质中苯乙胺部分的苯环的最佳取代模式，这一特征迄今为止主要在衍生自 -位的苯乙胺中得到探索。在使用的生物测定中，最有效的物质是 24H-NBF（EC 值为 158 nM）、26H-NBF（397 nM）和 25H-NBF（448 nM），而 23H-NBF、35H-NBF 和 34H-NBF 的 EC 值为 μM。化合物的效价也得到了类似的排名：以 LSD（麦角酸二乙酰胺）为参考，24H-、26H-和 25H-NBF 的效价为 106-107%，其次是 23H-NBF（96.1%）、34H-NBF（75.2%）和 35H-NBF（58.9%）。24H-、25H-和 26H-NBF 的更强活性强调了苯乙胺部分 2 位甲氧基对 NBF 物质功能的重要作用。
