Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions

Cannabinoid ligands are known to possess neuroprotective actions and may have utility in the treatment of neurodegeneration. The major targets for cannabinoids include the classical CB1 cannabinoid receptor, as well as the novel cannabinoid receptor GPR55 which binds to many synthetic cannabinoid li...

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Main Authors: J. Senkiv, A. Kryshchyshyn-Dylevych, D. Khylyuk, M. Wujec, R. Stoika, A. J. Irving, R. Lesyk
Format: Article
Language:English
Published: National Academy of Sciences of Ukraine, Palladin Institute of Biochemistry 2023-02-01
Series:The Ukrainian Biochemical Journal
Subjects:
Online Access:http://ukrbiochemjournal.org/wp-content/uploads/2023/04/Senkiv_95_1.pdf
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author J. Senkiv
A. Kryshchyshyn-Dylevych
D. Khylyuk
M. Wujec
R. Stoika
A. J. Irving
R. Lesyk
author_facet J. Senkiv
A. Kryshchyshyn-Dylevych
D. Khylyuk
M. Wujec
R. Stoika
A. J. Irving
R. Lesyk
author_sort J. Senkiv
collection DOAJ
description Cannabinoid ligands are known to possess neuroprotective actions and may have utility in the treatment of neurodegeneration. The major targets for cannabinoids include the classical CB1 cannabinoid receptor, as well as the novel cannabinoid receptor GPR55 which binds to many synthetic cannabinoid ligands. In this study, novel thiopyranothiazoles 1, 3, 4, 6, and 7 were synthesized and their pharmacological activity as potential cannabinoid-like ligands was evaluated in glioblastoma cells, cultured cortical neurons, and cells of HEK293 line expressing GPR55. Stimulation of protein kinase ERK1/2, MAP-kinases and cAMP response element binding protein (CREB) was evaluated using Western-blot analysis. CREB activation was additionally monitored by means of confocal imaging of nuclear phospho-CREB labeling. Docking simulation confirmed the good affinity of the synthesized compounds to CB1 and CB2 receptors. Striking effects of the chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3]thiazol with ethylacetate moiety (3) and isothiochromeno[4a,4-d]thiazole with phenazone fragment (7) on pCREB activation as the indicator of stimulation of the pathway beneficial for neurons survival were observed.
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spelling doaj.art-bdb3db9398744c3fb8c066fadd3140832023-10-16T11:32:19ZengNational Academy of Sciences of Ukraine, Palladin Institute of BiochemistryThe Ukrainian Biochemical Journal2409-49432413-50032023-02-01951314310.15407/ubj95.01.031Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functionsJ. Senkiv0https://orcid.org/0000-0002-0587-3850A. Kryshchyshyn-Dylevych1https://orcid.org/0000-0002-8713-7020D. Khylyuk2https://orcid.org/0000-0001-9306-7463M. Wujec3https://orcid.org/0000-0001-9816-1934R. Stoika4https://orcid.org/0000-0001-5719-2187A. J. Irving5R. Lesyk6Department of Regulation Cell Proliferation and Apoptosis, Institute of Cell Biology, National Academy of Sciences of Ukraine, LvivDepartment of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, UkraineDepartment of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, Lublin, PolandDepartment of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, Lublin, PolandDepartment of Regulation Cell Proliferation and Apoptosis, Institute of Cell Biology, National Academy of Sciences of Ukraine, LvivSchool of Biomedical and Biomolecular Science, University College of Dublin, Dublin, IrelandDepartment of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine; Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Rzeszow, PolandCannabinoid ligands are known to possess neuroprotective actions and may have utility in the treatment of neurodegeneration. The major targets for cannabinoids include the classical CB1 cannabinoid receptor, as well as the novel cannabinoid receptor GPR55 which binds to many synthetic cannabinoid ligands. In this study, novel thiopyranothiazoles 1, 3, 4, 6, and 7 were synthesized and their pharmacological activity as potential cannabinoid-like ligands was evaluated in glioblastoma cells, cultured cortical neurons, and cells of HEK293 line expressing GPR55. Stimulation of protein kinase ERK1/2, MAP-kinases and cAMP response element binding protein (CREB) was evaluated using Western-blot analysis. CREB activation was additionally monitored by means of confocal imaging of nuclear phospho-CREB labeling. Docking simulation confirmed the good affinity of the synthesized compounds to CB1 and CB2 receptors. Striking effects of the chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3]thiazol with ethylacetate moiety (3) and isothiochromeno[4a,4-d]thiazole with phenazone fragment (7) on pCREB activation as the indicator of stimulation of the pathway beneficial for neurons survival were observed.http://ukrbiochemjournal.org/wp-content/uploads/2023/04/Senkiv_95_1.pdfcamp response element binding protein (creb)cb1cb2cultured cortical neuronsputative cannabinoid ligandsthiopyranothiazoles
spellingShingle J. Senkiv
A. Kryshchyshyn-Dylevych
D. Khylyuk
M. Wujec
R. Stoika
A. J. Irving
R. Lesyk
Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
The Ukrainian Biochemical Journal
camp response element binding protein (creb)
cb1
cb2
cultured cortical neurons
putative cannabinoid ligands
thiopyranothiazoles
title Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
title_full Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
title_fullStr Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
title_full_unstemmed Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
title_short Novel putative ligands of cannabinoid receptors: synthesis and effects on cell signaling and neuronal functions
title_sort novel putative ligands of cannabinoid receptors synthesis and effects on cell signaling and neuronal functions
topic camp response element binding protein (creb)
cb1
cb2
cultured cortical neurons
putative cannabinoid ligands
thiopyranothiazoles
url http://ukrbiochemjournal.org/wp-content/uploads/2023/04/Senkiv_95_1.pdf
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