YZG-331 is a synthetic novel derivates of N6-(4-hydroxybenzyl) adenine riboside (NHBA), which has potent sedative and hypnotic effects based on our previous study. We are now aiming to investigate the mechanism of YZG-331. In this research, the behavioral studies showed that YZG-331 (4, 8, 16 mg/kg, i.g.) could reduce the spontaneous locomotor activity in mice, which could be blocked by AM (non-selective adenosine receptor antagonist), DPCPX (adenosine A1 receptor (A1R) antagonist), and SCH58261 (adenosine A2a receptor (A2aR) antagonist). Moreover, YZG-331 no longer exerted sedative effect in A1R or A2aR knockdown mice. YZG-331 (2.5, 5, 10 mg/kg, i.g.) prolonged sleeping time in pentobarbital sodium treated mice, which can be prevented by DPCPX or SCH58261. The above results demonstrated that YZG-331 exerted sedative and hypnotic effects through A1R and A2aR. In addition, it was found that YZG-331 (25, 50, 100 μM) decreased intracellular calcium level and YZG-331 (10 mg/kg, i.g.) decreased CaMKII phosphorylation (pCaMKII) level in mouse hypothalamus and cortex. In summary, this study indicated that activation of A1R/ A2aR and down regulation of Ca2+-CaMKII signaling pathway were involved in the sedative and hypnotic effects of YZG-331.
Keywords: A(1)R; A(2a)R; PCaMKII; Sedative hypnotic; YZG-331.
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