Morimoto H, Murai M, Maeda Y, Yamaoka M, Nishikawa M, Kiyotoh S, Fujii T
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
J Pharmacol Exp Ther. 1992 Jul;262(1):398-402.
We have discovered a novel cyclopeptide substance P (SP) antagonist, FK 224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L-allo- threonyl]-L-asparaginyl]-L-serine-nu-lactone), which inhibited [3H]SP binding to guinea pig lung membranes in a dose-dependent manner. According to Rosenthal analysis, the inhibitory effect of FK 224 on [3H]SP binding appears to be competitive. In order to clarify the receptor subtype selectivity of FK 224, we have studied the interaction of FK 224 with three tachykinin receptors (NK1, NK2 and NK3) by using receptor binding techniques and in vitro bioassays, and have also compared FK 224 with the novel nonpeptide antagonist, (+/-)-CP-96,345. In binding experiments, FK 224 dose-dependently inhibited [3H]SP binding to rat cerebral cortical membranes (NK1) and [3H]neurokinin (NK) A (NKA) binding to rat duodenum smooth muscle membranes (NK2), but did not affect [3H]eledoisin binding to rat cerebral cortical membranes (NK3). In bioassay experiments, FK 224 inhibited SP-induced contraction of guinea pig ileum (NK1) and NKA-induced contraction of rat vas deferens (NK2) in a dose-dependent manner, but did not affect NKB-induced contraction of rat portal vein (NK3). In contrast, (+/-)-CP-96,345 inhibited SP-induced contraction of guinea pig ileum, but not NKA-induced contraction of rat vas deferens or NKB-induced contraction of rat portal vein. In the presence of FK 224, SP dose-response curves and NKA dose-response curves were shifted to the right in parallel with no depression of the maximal contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
我们发现了一种新型环肽物质P（SP）拮抗剂FK 224（N-[N2-[N-[N-[N-[2,3-二脱氢-N-甲基-N-[N-[3-(2-戊基苯基)-丙酰基]-L-苏氨酰基]酪氨酰-L-亮氨酰基]-D-苯丙氨酰基]-L-别苏氨酰基]-L-天冬酰胺基]-L-丝氨酸-ν-内酯），它能以剂量依赖方式抑制[3H]SP与豚鼠肺膜的结合。根据罗森塔尔分析，FK 224对[3H]SP结合的抑制作用似乎具有竞争性。为了阐明FK 224的受体亚型选择性，我们利用受体结合技术和体外生物测定法研究了FK 224与三种速激肽受体（NK1、NK2和NK3）的相互作用，并且还将FK 224与新型非肽拮抗剂(+/-)-CP-96,345进行了比较。在结合实验中，FK 224以剂量依赖方式抑制[3H]SP与大鼠大脑皮质膜（NK1）的结合以及[3H]神经激肽（NK）A（NKA）与大鼠十二指肠平滑肌膜（NK2）的结合，但不影响[3H]伊勒多辛与大鼠大脑皮质膜（NK3）的结合。在生物测定实验中，FK 224以剂量依赖方式抑制SP诱导的豚鼠回肠收缩（NK1）和NKA诱导的大鼠输精管收缩（NK2），但不影响NKB诱导的大鼠门静脉收缩（NK3）。相比之下，(+/-)-CP-96,345抑制SP诱导的豚鼠回肠收缩，但不抑制NKA诱导的大鼠输精管收缩或NKB诱导的大鼠门静脉收缩。在FK 224存在的情况下，SP剂量反应曲线和NKA剂量反应曲线平行右移，最大收缩无降低。（摘要截短至250字）
