Evaluation of 3, 4, 5-Trimethoxycinnamic Acid Derivatives as Potential Antinarcotic and Anxiolytic Agents

To determine the biological activity of natural products for antinarcotics and anxiolytics, Polygala tenuifolia was selected as an interesting natural resources. 3, 4, 5-Trimethoxycinnamic acid (TMCA) was an ingredient from Polygala tenuifolia and a series of TMCA derivatives was prepared and evaluated for antinarcotic effects on morphine dependence in mice and binding affinities on serotonergic receptors. The key synthetic strategies involve generation of ketones, esters through condensation reaction, and amides via coupling reaction using HOBt/EDCI system in high yield. We found that the naloxone-induced morphine withdrawal syndrome was significantly suppressed by new synthetic TMCA derivatives (20 mg/kg/day). Most of TMCA derivatives were found to have high affinity to 5-HT_1A receptor. Interestingly, the TMCA derivatives showed inhibitory action to the anxiety which was induced by restraint stress in mice. These results suggested that new synthetic TMCA derivatives have a potential antinarcotic and anxiolytic effect in mice.