Serotonin 2A Receptor (5-HT2AR) Activation by 25H-NBOMe Positional Isomers: In Vitro Functional Evaluation and Molecular Docking

• DOI: 10.1021/acsptsci.0c00189
• Publication Date: 2021-02-25T21:51:11Z
• Authors: Eline Pottie; Olga V. Kupriyanova; Asher L. Brandt; Robert B. Laprairie; Vadim A. Shevyrin; Christophe P. Stove
• Keywords: Moiety; Phenethylamines; Phenethylamines; Docking (animal)

Serotonergic psychedelics are defined as compounds having serotonin 2A receptor (5-HT2AR) activation an important pharmacological mechanism. These include the phenylalkylamine class, containing substances with e.g. 2C-X structures (phenethylamines) or their N-methoxybenzyl analogues (NBOMes). Besides abuse potential, increasingly recognized for therapeutic benefits. However, many remain incompletely characterized, even concerning structure-activity relationships. Here, five positional isomers of 25H-NBOMe, two methoxy groups on different positions phenyl ring phenethylamine moiety, were subjected to split-nanoluciferase assays assessing in vitro recruitment cytosolic proteins 5-HT2AR. Furthermore, molecular docking at 5-HT2AR allowed estimation which residues interact specific isomers' groups. Although optimal substitution pattern N-unsubstituted phenylalkylamines has been extensively studied, this is first comparative evaluation functional effects positioning moiety NBOMes.