Novel Chromone-Containing Allylmorpholines Induce Anxiolytic-like and Sedative Effects in Adult Zebrafish

Veronika A Prikhodko; Yuri I Sysoev; Elena V Gerasimova; Sergey V Okovityi

doi:10.3390/biomedicines10112783

Novel Chromone-Containing Allylmorpholines Induce Anxiolytic-like and Sedative Effects in Adult Zebrafish

Biomedicines. 2022 Nov 2;10(11):2783. doi: 10.3390/biomedicines10112783.

Authors

Veronika A Prikhodko^{1

2}, Yuri I Sysoev^{1

2

3

4

5}, Elena V Gerasimova⁴, Sergey V Okovityi^{1

2}

Affiliations

¹ Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 197376 Saint Petersburg, Russia.
² Laboratory of Targeted Intra-Brain Drug Delivery, N.P. Bechtereva Institute of the Human Brain of the Russian Academy of Sciences, 197376 Saint Petersburg, Russia.
³ Laboratory of Neuromodulation of Motor and Visceral Functions, I.P. Pavlov Institute of Physiology of the Russian Academy of Sciences, 199034 Saint Petersburg, Russia.
⁴ Department of Neurobiology, Sirius University of Science and Technology, 353340 Sochi, Russia.
⁵ Institute of Translational Biomedicine, Saint Petersburg State University, 199034 Saint Petersburg, Russia.

Abstract

Chromone-containing allylmorpholines (CCAMs) are a novel class of compounds that have demonstrated acetyl- and butyryl-cholinesterase-inhibiting and N-methyl-D-aspartate (NMDA) receptor-blocking properties in vitro, but their in vivo pharmacological activity remains underexplored. In this work, we evaluated the psychotropic activity of five different CCAMs (1 (9a), 2 (9j), 3 (9l), 4 (33a), and 5 (33b)) using the novel tank test (NTT) and light/dark box (LDB) test in adult zebrafish. The CCAMs were screened in the NTT at a range of concentrations, and they were found to induce a dose-dependent sedative effect. Compound 4 (33a) was also evaluated using the LDB test, and it was found to have anxiolytic-like properties at low concentrations. To assess the potential contribution of the glutamate and cholinergic mechanisms in the effects of the CCAMs, we conducted experiments with pre-exposure to putative antagonists, NMDA and biperiden. Neither biperiden nor NMDA were able to diminish or cancel the effects of the CCAMs, countering the in vitro data obtained in previous studies. The apparent discrepancy could be related to the specifics of CCAM metabolism or to the interspecies differences between the putative target proteins, possibly due to the relatively low identity percentage of their sequences. Although further research in mammals is required in order to establish their pharmacological properties, novel CCAMs may represent an appealing group of psychoactive drug candidates.

Keywords: NMDA receptors; acetylcholinesterase; allylmorpholines; anxiolytics; behavioral testing; chromone derivatives; morpholine derivatives; novel tank test; sedatives; zebrafish.

Abstract

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