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.