〔Abstract〕 Objective To explore the effect of(-)-meptazinol-serotonin hybrid, [(-)-Mep-S] on scopolamine-induced learning and memory impairment in mice. Methods The binding of(-)-Mep-S and hAChE was analyzed by molecular docking. The effect of(-)-Mep-S on AChE activity was observed in vivo and in vitro. The effect of(-)-Mep-S on learning and memory impairment induced by scopolamine was examined in Morris water maze test in mice. The effect of(-)-Mep-S on the motor behaviors of mice was detected by open field test. Results Molecular docking analysis revealed that(-)-Mep-S binded to human AChE. In parallel,(-)-Mep-S overtly inhibited the activity of AChE derived from mouse forebrain and SH-SY5Y neuronal cells, and IC50 values were lower than those of the positive control drug rivastigmine. In the Morris water maze test, mice treated with(-)-Mep-S(2.5 mg/kg) showed significantly reduced latency on day 4(P<0.05). Moreover, they exhibited significantly greater percentage of distance travelled and percentage of time spent in the target quadrant in the probe trial on day 5(P<0.05).(-)-Mep-S at 0.5 mg/kg did not show any significant effects. In addition,(-)-Mep-S inhibited the enhancement of forebrain AChE activity induced by scopolamine(P<0.05). The open field test showed that the effect of(-)-Mep-S on scopolamine-induced learning and memory impairment was not due to the difference on the motor behaviors of mice. Conclusion(-)-Mep-S can effectively inhibit AChE activity and ameliorate scopolamine-induced learning and memory impairment in mice.