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 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. Keywords: cAMP response element binding protein (CREB), CB1, CB2, cultured cortical neurons, putative cannabinoid ligands, thiopyranothiazoles