Abstract
The effects of KB-2796, a new Ca2+-channel blocker, on 5-hydroxytryptamine (5-HT)-induced responses were investigated in comparison with those of other Ca2+-channel blockers such as verapamil, flunarizine, diltiazem and nimodipine. In rat cortical membrane, KB-2796 inhibited specific [3H] spiperone binding to 5-HT2 receptors in a competitive manner (Ki = 0.57 μM), but exhibited negligible affinity for radioligand binding to other 5-HT receptor subtypes such as 5-HT1, 5-HT1A, 5-HT1B, 5-HT1C and 5-HT3 at a concentration of 10 or 100 μM. KB-2796 inhibited both 5-HT-stimulated shape change and 5-HT and collagen-stimulated aggregation in rabbit platelet-rich plasma with IC50 values of 13.4 μM and 96.4 μM, respectively. KB-2796 also inhibited the 5-HT-induced increase of [Ca2+]i, in washed rabbit platelets with the IC50 value of 25.7 μM. Furthermore, KB-2796 (3-30 mg/kg, p.o.) dose-dependently inhibited the 5-HT-induced paw edema in rats. In these experiments, the inhibitory effects of KB-2796 and other Ca2+ channel blockers were related to their affinities for the 5-HT2 receptor; and the potency of KB-2796 was stronger than those of diltiazem and nimodipine and almost equal to that of flunarizine, although all these inhibitors had weaker potencies than that of verapamil. These findings indicate that KB-2796 may possess antagonistic effect on the 5-HT2 receptor.
