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

Konstantin A Demin; Olga V Kupriyanova; Vadim A Shevyrin; Ksenia A Derzhavina; Nataliya A Krotova; Nikita P Ilyin; Tatiana O Kolesnikova; David S Galstyan; Yurii M Kositsyn; Abubakar-Askhab S Khaybaev; Maria V Seredinskaya; Yaroslav Dubrovskii; Raziya G Sadykova; Maria O Nerush; Mikael S Mor; Elena V Petersen; Tatyana Strekalova; Evgeniya V Efimova; Savelii R Kuvarzin; Konstantin B Yenkoyan; Dmitrii V Bozhko; Vladislav O Myrov; Sofia M Kolchanova; Aleksander I Polovian; Georgii K Galumov; Allan V Kalueff

doi:10.1021/acschemneuro.2c00123

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

ACS Chem Neurosci. 2022 Jul 6;13(13):1902-1922. doi: 10.1021/acschemneuro.2c00123. Epub 2022 Jun 7.

Authors

Konstantin A Demin^{1

2}, Olga V Kupriyanova^{3

4}, Vadim A Shevyrin⁵, Ksenia A Derzhavina^{1

2}, Nataliya A Krotova^{1

2}, Nikita P Ilyin^{1

2}, Tatiana O Kolesnikova^{1

6}, David S Galstyan^{1

7}, Yurii M Kositsyn¹, Abubakar-Askhab S Khaybaev², Maria V Seredinskaya¹, Yaroslav Dubrovskii^{2

8

9}, Raziya G Sadykova⁴, Maria O Nerush², Mikael S Mor¹, Elena V Petersen¹⁰, Tatyana Strekalova¹¹, Evgeniya V Efimova¹, Savelii R Kuvarzin¹, Konstantin B Yenkoyan^{12

13}, Dmitrii V Bozhko¹⁴, Vladislav O Myrov¹⁴, Sofia M Kolchanova¹⁴, Aleksander I Polovian¹⁴, Georgii K Galumov¹⁴, Allan V Kalueff^{1

2

15

16

10

13

17}

Affiliations

¹ Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russia.
² Almazov National Medical Research Centre, St. Petersburg 197341, Russia.
³ Institute of Fundamental Medicine and Biology, Kazan Volga Region Federal University, Kazan 420008, Russia.
⁴ Kazan State Medical University, Kazan 420012, Russia.
⁵ Institute of Chemistry and Technology, Ural Federal University, 19 Mira Str., Ekaterinburg 620002, Russia.
⁶ Neurobiology Program, Sirius University of Science and Technology, Sochi 354340, Russia.
⁷ Laboratory of Preclinical Bioscreening, Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny 197758, Russia.
⁸ Institute of Chemistry, St. Petersburg State University, St. Petersburg 199034, Russia.
⁹ St. Petersburg State Chemical Pharmaceutical University, St. Petersburg 197022, Russia.
¹⁰ Moscow Institute of Physics and Technology, Moscow 141701, Russia.
¹¹ Maastricht University, NL Postbus 616, Maastricht 62, Netherlands.
¹² Neuroscience Laboratory, COBRAIN Center, M. Heratsi Yerevan State Medical University, Yerevan AM 0025, Armenia.
¹³ COBRAIN Scientific Educational Center for Fundamental Brain Research, Yerevan AM 0025, Armenia.
¹⁴ ZebraML, Inc., Houston 77001 Texas, United States.
¹⁵ Ural Federal University, Ekaterinburg 620075, Russia.
¹⁶ Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny 197758, Russia.
¹⁷ Scientific Research Institute of Neuroscience and Medicine, Novosibirsk, 630117, Russia.

PMID: 35671176
DOI: 10.1021/acschemneuro.2c00123

Abstract

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.

Keywords: AI-phenotyping; behavior; in silico drug activity; novel compounds; psychopharmacology; zebrafish.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Artificial Intelligence
Behavior, Animal
Hallucinogens* / chemistry
Hallucinogens* / pharmacology
Phenethylamines / chemistry
Phenethylamines / pharmacology
Zebrafish

Substances

Hallucinogens
Phenethylamines
phenethylamine