posted on 2021-02-25, 22:04authored byEline Pottie, Olga V. Kupriyanova, Asher L. Brandt, Robert B. Laprairie, Vadim A. Shevyrin, Christophe P. Stove
Serotonergic
psychedelics are defined as compounds having serotonin
2A receptor (5-HT2AR) activation as an important pharmacological
mechanism. These compounds include the phenylalkylamine class, containing
substances with e.g. 2C-X structures (phenethylamines) or their N-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 in vitro recruitment of cytosolic proteins to the 5-HT2AR. Furthermore, molecular docking at the 5-HT2AR allowed estimation of which residues interact with the specific
isomers’ methoxy groups. Although the optimal substitution
pattern of N-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.