TY - JOUR

T1 - Novel chromone-containing allylmorpholines induce anxiolytic-like and sedative effects in adult zebrafish

AU - Приходько, Вероника

AU - Сысоев, Юрий Игоревич

AU - Герасимова, Елена

AU - Оковитый, С.В.

N1 - Publisher Copyright: © 2022 by the authors.

PY - 2022/11/2

Y1 - 2022/11/2

N2 - 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.

AB - 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.

KW - NMDA receptors

KW - acetylcholinesterase

KW - allylmorpholines

KW - anxiolytics

KW - behavioral testing

KW - chromone derivatives

KW - morpholine derivatives

KW - novel tank test

KW - sedatives

KW - zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85141885362&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/d0663fd0-5681-316c-bd1c-446fc2c7f15c/

U2 - 10.3390/biomedicines10112783

DO - 10.3390/biomedicines10112783

M3 - Article

VL - 10

JO - Biomedicines

JF - Biomedicines

SN - 2227-9059

IS - 11

M1 - 2783

ER -