Ferutinin (1), the major constituent of Ferula hermonis and other Ferula species, is a sesquiterpene ester with remarkable estrogenic activity, beside other valuable medicinal properties. To investigate the influence of chemical modification of the ferutinin structure on its estrogenic effect and binding affinity toward the cannabinoid CB1 and CB2 receptors, twelve derivatives of 1 were prepared and evaluated in vitro, together with the parent compound, for the respective bioactivities, based on the recent evidence for estrogen–endocannabinoid interaction. Nine of the prepared derivatives (3–11) are new semisynthetic esters of 1. The parent compound ferutinin (1) exhibited the highest level of estrogenic activity (EC50 0.3 μM and a percent maximal 17β-estradiol response of 90 % at 1 µM). Compound 6 was found to be a selective agonist for CB2 receptor (EC50 0.051 μM, Ki 0.025 μM), with much less affinity for CB1 receptor (EC50 97 μM, Ki 48.5 μM). Compound 8 was a selective agonist for CB1 (EC50 62, Ki 0.031 μM) with no affinity toward CB2.