TY - JOUR

T1 - Acute behavioral and Neurochemical Effects of Novel N-Benzyl-2-Phenylethylamine Derivatives in Adult Zebrafish

AU - Demin, Konstantin A

AU - Kupriyanova, Olga V

AU - Shevyrin, Vadim A

AU - Derzhavina, Ksenia A

AU - Krotova, Nataliya A

AU - Ilyin, Nikita P

AU - Kolesnikova, Tatiana O

AU - Galstyan, David S

AU - Kositsyn, Yurii M

AU - Khaybaev, Abubakar-Askhab S

AU - Seredinskaya, Maria V

AU - Dubrovskii, Yaroslav

AU - Sadykova, Raziya G

AU - Nerush, Maria O

AU - Mor, Mikael S

AU - Petersen, Elena V

AU - Strekalova, Tatyana

AU - Efimova, Evgeniya V

AU - Kuvarzin, Savelii R

AU - Yenkoyan, Konstantin B

AU - Bozhko, Dmitrii V

AU - Myrov, Vladislav O

AU - Kolchanova, Sofia M

AU - Polovian, Aleksander I

AU - Galumov, Georgii K

AU - Kalueff, Allan V

N1 - Publisher Copyright: © 2022 American Chemical Society.

PY - 2022/7/6

Y1 - 2022/7/6

N2 - Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel 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 the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H-NBOMe(F) and 34H-NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, 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)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.

AB - Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel 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 the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H-NBOMe(F) and 34H-NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, 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)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.

KW - AI-phenotyping

KW - behavior

KW - in silico drug activity

KW - novel compounds

KW - psychopharmacology

KW - zebrafish

UR - https://www.mendeley.com/catalogue/a6d5e286-b6fd-33f6-9f24-ac98ca83189d/

UR - http://www.scopus.com/inward/record.url?scp=85133475586&partnerID=8YFLogxK

U2 - 10.1021/acschemneuro.2c00123

DO - 10.1021/acschemneuro.2c00123

M3 - Article

C2 - 35671176

VL - 13

SP - 1902

EP - 1922

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 13

ER -