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Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish

View ORCID ProfileKonstantin A. Demin, Olga V. Kupriyanova, Vadim A. Shevyrin, Ksenia A. Derzhavina, Nataliya A. Krotova, Nikita P. Ilyin, Tatiana O. Kolesnikova, David S. Galstyan, Iurii 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, Dmitrii V. Bozhko, Vladislav O. Myrov, Sofia M. Kolchanova, Aleksander I. Polovian, Georgii K. Galumov, Allan V. Kalueff
doi: https://doi.org/10.1101/2022.01.19.476767
Konstantin A. Demin
1Almazov National Medical Research Centre, St. Petersburg, Russia
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
11Neurobiology Program, Sirius University, Sochi, Russia
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  • ORCID record for Konstantin A. Demin
  • For correspondence: avkalueff@gmail.com deminkasci@gmail.com
Olga V. Kupriyanova
3Institute of Fundamental Medicine and Biology, Kazan Volga Region Federal University, Kazan, Russia
4Kazan State Medical University, Kazan, Russia
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Vadim A. Shevyrin
5Institute of Chemistry and Technology, Ural Federal University, 19 Mira Str., 620002, Ekaterinburg, Russia
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  • For correspondence: avkalueff@gmail.com deminkasci@gmail.com
Ksenia A. Derzhavina
1Almazov National Medical Research Centre, St. Petersburg, Russia
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Nataliya A. Krotova
1Almazov National Medical Research Centre, St. Petersburg, Russia
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Nikita P. Ilyin
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Tatiana O. Kolesnikova
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
11Neurobiology Program, Sirius University, Sochi, Russia
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David S. Galstyan
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
6Laboratory of Preclinical Bioscreening, Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia
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Iurii M. Kositsyn
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Abubakar-Askhab S. Khaybaev
1Almazov National Medical Research Centre, St. Petersburg, Russia
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Maria V. Seredinskaya
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Yaroslav Dubrovskii
1Almazov National Medical Research Centre, St. Petersburg, Russia
7St. Petersburg State University, Institute of Chemistry, St. Petersburg, Russia
8St. Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia
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Raziya G. Sadykova
4Kazan State Medical University, Kazan, Russia
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Maria O. Nerush
1Almazov National Medical Research Centre, St. Petersburg, Russia
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Mikael S. Mor
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Elena V. Petersen
13Moscow Institute of Physics and Technology, Moscow, Russia
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Tatyana Strekalova
14Maastricht University, Maastricht, Netherlands
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Evgeniya V. Efimova
2Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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Dmitrii V. Bozhko
15ZebraML, Inc., Houston, TX, USA
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Vladislav O. Myrov
15ZebraML, Inc., Houston, TX, USA
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Sofia M. Kolchanova
15ZebraML, Inc., Houston, TX, USA
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Aleksander I. Polovian
15ZebraML, Inc., Houston, TX, USA
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Georgii K. Galumov
15ZebraML, Inc., Houston, TX, USA
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Allan V. Kalueff
9School of Pharmacy, Southwest University, Chongqing, China
10Ural Federal University, Ekaterinburg, Russia
12Granov Russian Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia
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  • For correspondence: avkalueff@gmail.com deminkasci@gmail.com
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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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 21, 2022.
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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, Iurii 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, Dmitrii V. Bozhko, Vladislav O. Myrov, Sofia M. Kolchanova, Aleksander I. Polovian, Georgii K. Galumov, Allan V. Kalueff
bioRxiv 2022.01.19.476767; doi: https://doi.org/10.1101/2022.01.19.476767
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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, Iurii 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, Dmitrii V. Bozhko, Vladislav O. Myrov, Sofia M. Kolchanova, Aleksander I. Polovian, Georgii K. Galumov, Allan V. Kalueff
bioRxiv 2022.01.19.476767; doi: https://doi.org/10.1101/2022.01.19.476767

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