PT  - JOURNAL ARTICLE
AU  - Konstantin A. Demin
AU  - Olga V. Kupriyanova
AU  - Vadim A. Shevyrin
AU  - Ksenia A. Derzhavina
AU  - Nataliya A. Krotova
AU  - Nikita P. Ilyin
AU  - Tatiana O. Kolesnikova
AU  - David S. Galstyan
AU  - Iurii M. Kositsyn
AU  - Abubakar-Askhab S. Khaybaev
AU  - Maria V. Seredinskaya
AU  - Yaroslav Dubrovskii
AU  - Raziya G. Sadykova
AU  - Maria O. Nerush
AU  - Mikael S. Mor
AU  - Elena V. Petersen
AU  - Tatyana Strekalova
AU  - Evgeniya V. Efimova
AU  - Dmitrii V. Bozhko
AU  - Vladislav O. Myrov
AU  - Sofia M. Kolchanova
AU  - Aleksander I. Polovian
AU  - Georgii K. Galumov
AU  - Allan V. Kalueff
TI  - Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish
AID  - 10.1101/2022.01.19.476767
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.19.476767
4099  - http://biorxiv.org/content/early/2022/01/21/2022.01.19.476767.short
4100  - http://biorxiv.org/content/early/2022/01/21/2022.01.19.476767.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.