Cinnamophilin, a novel thromboxane A₂ receptor antagonist, isolated from Cinnamomum philippinense

The pharmacological activity of cinnamophilin ((8R,8′S)-4,4′-dihydroxy-3,3′-dimethoxy-7-oxo-8,8 ′-neolignan), isolated from Cinnamomum philippinense, was studied in isolated rat aorta, guinea-pig trachea and rabbit platelets. Cinnamophilin was found to be a thromboxane A₂ receptor blocking agent in these tissues as revealed by its competitive antagonism of the U-46619 (9,11-dideoxymethanoepoxy-9α,11α-prostaglandin F_2α)-induced contraction of rat aorta and guinea-pig trachea and aggregation of rabbit platelets with pA₂ values of 7.3±0.2, 5.2±0.1 and 6.3±0.3, respectively. Protection against the irreversible vasoconstriction of rat aorta caused by U-46619 (0.05 μM) was obtained by cinnamophilin (10 μM) but not by caffeine (25 mM). Cinnamophilin (1-15 μM) also possessed voltage-dependent Ca²⁺ channel blocking action, judging from its antagonism of the high K⁺ (60 mM)- and Bay K 8644 (0.1 μM)-induced contraction in rat thoracic aorta. Cinnamophilin (30 μM) produced a slight relaxation of noradrenaline (3 μM)-induced tonic contractions, and this relaxing effect was abolished in the presence of nifedipine (1 μM). Nifedipine (10 μM) sufficient to inhibit high K⁺-induced contractions failed to attenuate the contractile response to U-46619. A high concentration of cinnamophilin (100 μM) did not affect the aortic contraction induced by endothelin-1, angiotensin II, carbachol or serotonin. Neither cAMP nor cGMP in rat aorta was increased by cinnamophilin. These results indicate that cinnamophilin is a selective thromboxane A₂ receptor antagonist especially in rat aorta, and also possesses voltage-dependent Ca²⁺ channel blocking properties.