Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish
Konstantin A. Demin, Olga V. Kupriyanova, Вадим А. Шевырин, Ksenia A. Derzhavina, Nataliya A. Krotova, Nikita P. Ilyin, Tatiana O. Kolesnikova, David S. Galstyan, Iurii M. Kositsyn, Abubakar-askhab S. Khaybaev, Maria Seredinskaya, Yaroslav A. Dubrovskii, Raziya G. Sadykova, Maria O. Nerush, Mikael S. Mor, Elena V. Petersen, Tatyana Strekalova, Evgeniya Efimova, Dmitrii V. Bozhko, Vladislav Myrov, Sofia M. Kolchanova, Aleksander I. Polovian, Georgii K. Galumov, Allan V. Kalueff
bioRxiv (Cold Spring Harbor Laboratory) January 21, 2022 preprint DOI: 10.1101/2022.01.19.476767 via OpenAlex
Summary
Ten different N-Benzyl-2-phenylethylamine derivatives were tested in adult zebrafish to assess their effects on behavior and neurochemistry. The study found that these compounds influenced locomotion and anxiety-like behavior, with specific clusters identified, including anxiogenic/hypolocomotor and anxiolytic/hallucinogenic-like agents. Notably, two derivatives reduced despair-like behavior. The findings suggest potential clinical applications for these novel synthetic compounds due to their neuroactive properties.
Study at a glance
| Population | adult zebrafish |
|---|---|
| Key finding | Substitutions in the N-benzyl fragment affected zebrafish locomotion, while those in the phenethylamine moiety influenced anxiety-like behavior. |
Abstract
Abstract Serotonergic hallucinogenic drugs potently affect human brain and behavior, and have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing rodent studies, zebrafish ( Danio rerio ) is a powerful animal model for screening neuroactive drugs, including serotonergic agents. Here, we test ten different N-Benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the - OCH3, -OCF3, -F, -Cl and -Br substitutions in the ortho position of phenyl ring of N -benzyl fragment, assessing their behavioral and neurochemical effects in adult zebrafish. Overall, substitutions in N -benzyl fragment primarily affected zebrafish locomotion, and in phenethylamine moiety - anxiety-like behavior, also modulating brain serotonin and/or dopamine turnover. We also identified several behavioral clusters, including anxiogenic/hypolocomotor (24H-NBF, 24H-NBOMe and 34H-NBF), behaviorally inert (34H-NBBr, 34H-NBCl and 34H- NBOMe), anxiogenic/hallucinogenic-like (24H-NBBr, 24H-NBCl and 24H-NBOMe(F)), and anxiolytic/hallucinogenic-like (34H-NBOMe(F)) agents. The 24H-NBOMe(F) and 34H-NBOMe(F) also reduced despair-like behavior in zebrafish. The artificial intelligence-driven phenotyping supports association of multiple compounds with NMDA antagonists and/or MDMA, supporting their potential hallucinogenic-like properties, as well as other valuable psychoactive effects. In silico functional molecular activity modelling also supports existing of similarities between studied NBPEAs drugs, MDMA, and ketamine. Functional analysis implicates potential involvement of serotonin release stimulating activity, calcium channel (voltage-sensitive) activity, some serotonin receptors activity and variety of psychiatric and neurologic disorders treatments activities. Overall, we report potent neuroactive properties of several novel synthetic N -benzylphenylethylamines in an in vivo vertebrate model system (zebrafish), raising the possibility of their potential use in clinical practice.