Synthesis and Functional Characterization of 2-(2,5-Dimethoxyphenyl)-<i>N</i>-(2-fluorobenzyl)ethanamine (25H-NBF) Positional Isomers.

Abstract

Serotonergic psychedelics, substances exerting their pharmacological action through activation of the serotonin 2A receptor (5-HT_2AR), have continuously comprised a substantial fraction of the over 1000 reported New Psychoactive Substances (NPS) so far. Within this category, <i>N</i>-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 <i>in vitro</i> bioassay monitoring the recruitment of β-arrestin 2 to the 5-HT_2AR 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 <i>N</i>-benzyl derived substances, a feature so far mostly explored in the phenethylamines underived at the <i>N</i>-position. In the employed bioassay, the most potent substances were 24H-NBF (EC₅₀ value of 158 nM), 26H-NBF (397 nM), and 25H-NBF (448 nM), with 23H-NBF, 35H-NBF, and 34H-NBF yielding μM EC₅₀ 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 <i>in vitro</i> functionality of NBF substances.

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