Skimmianine and related furoquinolines function as antagonists of 5-hydroxytryptamine receptors in animals

1 Skimmianine, kokusaginine and confusameline, three furoquinolines extracted from the leaves of Evodia merrillii(Rutaceae), were investigated to characterize their selective effects on subtypes of 5-hydroxytryptamine (5-HT) receptors. 2 In the isolated membranes of rat cerebrocortex, using [³H]-5-HT and [³H]-ketanserin as radioligands, skimmianine and the two other furoquinolines displaced radioligand bindings in a concentration-dependent manner. Lower concentrations were required to affect [³H]-ketanserin binding than [³H]-5-HT binding in the order skimmianine > kokusaginine > confusameline. 3 Furoquinolines inhibited 5-HT-induced contraction mediated by 5-HT₂ receptors in the presence of methiothepin in rat isolated aorta. Also, the combination of furoquinolines with ketanserin showed an additive antagonism. 4 These furoquinolines were inactive on the 5-carboxamidotryptamine-induced relaxation of guinea-pig ileum, a 5-HT₁-mediated event. However, 5-HT-induced contraction via 5-HT₂ receptors was reduced by these furoquinolines in a way similar to that in blood vessels. 5 The failure of these compounds to affect the 5-HT-induced Bezold–Jarisch-like reflex in anaesthetized rats, the major .5-HT₃-mediated action, ruled out an action on 5-HT₃ receptors. 6 The results obtained suggest that three furoquinoline alkaloids may act on 5-HT receptors in animals, more selectively to the 5-HT₂ subtype, in the order of skimmianine > kokusaginine > confusameline.