Zebrafish larval behaviour study of cinnamic acid derivatives isolated from <i>cannabis sativa</i> roots and their synthetic analogs

Chemical investigation of <i>Cannabis sativa</i> roots led us to the isolation of three phenolic compounds, namely <i>p</i>-coumaric acid methyl ester (<b>1</b>), <i>N</i>-<i>p</i>-coumaroyltyramine (<b>2</b>) and <i>N</i>-<i>p</i>-coumaroyloctopamine (<b>3</b>). Among the isolated phenolics, <b>3</b> was the first report from cannabis roots. To perform a structure-activity relationship study a series of cinnamide analogs were synthesised and tested using the zebrafish larval behavioural model. Increased locomotor activities were observed for <b>3</b> and some synthetic cinnamide analogues during the first 50 min following exposures at a 30 µM concentration. The zebrafish larval behaviour effects of these cinnamides differ from those of the two principal cannabinoids of <i>C. sativa</i>, cannabidiol and Δ⁹-tetrahydrocannabinol, which were well studied for their medicinal applications. The structure-activity relationship study clearly demonstrates the amide or ester bond is essential for such activity, as none of the free cinnamic acid derivatives tested showed zebrafish behaviour activity as compared to the control group.