抄録
Progress in the characterization of tachykinin receptors and the understanding of the physiological and pathological roles of tachykinins is highly dependent on the discovery of potent and selective antagonists with metabolic stability. We have recently described a peptidic antagonist of the tachykinin NK 1 receptor, sendide (Tyr-D-Phe-Phe-D-His-Leu-Met-NH2), that is a selective and extremely potent antagonist of NK-1 receptors, but displays no antagonistic activity on the response induced by NK-2 or NK-3-receptor agonists in the mouse spinal cord. When coadministered with substance P (SP) intrathecally (i.t.), sendide markedly inhibited the scratching, biting and licking behavior induced by SP in a dose-dependent manner. The antagonistic effect of sendide on the SP-induced behavioral response was approximately 7300 times more potent than that of CP-96, 345, a non-peptidic NK-1-receptor antagonist. The duration of the antagonistic effect of sendide was longer than that of CP-96, 345. The behavioral response elicited by other NK-1-receptor agonists, septide, physalaemin and [Sar9, Met (O2)11]-SP, was reduced significantly by a small dose of sendide. In the [3H]-SP binding assay using mouse spinal cord membranes, sendide potently displaced [3H]-SP binding, with a potency approximately 5.4×104 times greater than that of CP-96, 345. Moreover, Lt. administration of sendide was found to produce the antinociceptive effect through the blockage of NK-1 receptors in the mouse formalin and capsaicin tests. Sendide is therefore likely to become a powerful pharmacological tool for studying the functional roles of NK-1 receptors in the central nervous system.
