期刊
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
卷 4, 期 2, 页码 479-487出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.0c00189
关键词
bioassay; structure-activity relationship; serotonin receptor; molecular docking; psychedelic; new psychoactive substances
资金
- Research Foundation-Flanders (FWO) [G069419N, G0B8817N]
- Ghent University Special Research Fund (BOF) [01J15517]
- GlaxoSmithKline
- Canadian Institutes of Health Research (CIHR) [RN323670-386247]
- Russian Science Foundation [20-13-00089]
- [0671-2020-0058]
- Russian Science Foundation [20-13-00089] Funding Source: Russian Science Foundation
This study investigated the impact of five positional isomers of 25H-NBOMe on 5-HT2AR through experiments and molecular docking techniques. This is the first comparative evaluation of the functional effects of the positioning of methoxy groups in the phenethylamine moiety of NBOMes.
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.
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