Pottie Eline, Kupriyanova Olga V, Brandt Asher L, Laprairie Robert B, Shevyrin Vadim A, Stove Christophe P
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, Kazan 420008, Russian Federation.
ACS Pharmacol Transl Sci. 2021 Feb 25;4(2):479-487. doi: 10.1021/acsptsci.0c00189. eCollection 2021 Apr 9.
Serotonergic psychedelics are defined as compounds having serotonin 2A receptor (5-HTR) activation as an important pharmacological mechanism. These compounds include the phenylalkylamine class, containing substances with e.g. 2C-X structures (phenethylamines) or their -methoxybenzyl analogues (NBOMes). Besides their abuse potential, psychedelics are increasingly recognized for having therapeutic benefits. However, many psychedelics remain incompletely characterized, even concerning their structure-activity relationships. Here, five positional isomers of 25H-NBOMe, with two methoxy groups on the different positions of the phenyl ring of the phenethylamine moiety, were subjected to split-nanoluciferase assays assessing the recruitment of cytosolic proteins to the 5-HTR. Furthermore, molecular docking at the 5-HTR allowed estimation of which residues interact with the specific isomers' methoxy groups. Although the optimal substitution pattern of -unsubstituted phenylalkylamines has been extensively studied, this is the first comparative evaluation of the functional effects of the positioning of the methoxy groups in the phenethylamine moiety of NBOMes.
血清素能致幻剂被定义为以血清素2A受体（5 - HTR）激活作为重要药理机制的化合物。这些化合物包括苯基烷基胺类，含有例如具有2C - X结构的物质（苯乙胺）或其甲氧基苄基类似物（NBOMes）。除了其滥用潜力外，致幻剂因其具有治疗益处而越来越受到认可。然而，许多致幻剂甚至在其构效关系方面仍未得到充分表征。在此，对25H - NBOMe的五种位置异构体进行了研究，这些异构体在苯乙胺部分的苯环不同位置上有两个甲氧基，采用分裂纳米荧光素酶测定法评估胞质蛋白与5 - HTR的结合情况。此外，通过对5 - HTR进行分子对接，可以估计哪些残基与特定异构体的甲氧基相互作用。尽管对未取代的苯基烷基胺的最佳取代模式已进行了广泛研究，但这是首次对NBOMes苯乙胺部分中甲氧基位置的功能效应进行比较评估。
