J. Senkiv¹, A. Kryshchyshyn-Dylevych²*, D. Khylyuk³,
M. Wujec³, R. Stoika¹*, A. J. Irving⁴, R. Lesyk^2,5

¹Department of Regulation Cell Proliferation and Apoptosis, Institute of Cell Biology,
National Academy of Sciences of Ukraine, Lviv;
²Department of Pharmaceutical, Organic and Bioorganic Chemistry,
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
³Department of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division,
Medical University of Lublin, Lublin, Poland;
⁴School of Biomedical and Biomolecular Science, University College of Dublin, Dublin, Ireland;
⁵Department of Biotechnology and Cell Biology, Medical College,
University of Information Technology and Management in Rzeszow, Rzeszow, Poland;
*e-mail: stoika.rostyslav@gmail.com; kryshchyshyn.a@gmail.com

Received: 01 December 2022; Revised: 28 February 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023

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.