Croci T, Emonds-Alt X, Le Fur G, Manara L
SANOFI-MIDY S.p.A. Research Center, Milan, Italy.
Life Sci. 1995;56(4):267-75. doi: 10.1016/0024-3205(94)00921-x.
We investigated the potent non-peptide tachykinin receptor antagonists SR140333 and SR48968 for their ability to prevent the contraction of isolated intestinal tissues elicited by the non-selective agonists substance P (SP) and neurokinin A (NKA), or by [Sar9,Met(O2)11]SP and [beta-Ala8]NKA-(4-10) that are selective agonists for NK1 and NK2 receptors, respectively. In guinea-pig ileum, containing mainly NK1-receptors: SR140333 caused a pseudo-irreversible blockade of contractions induced by either SP (KB, 0.01 nM) or [Sar9,Met(O2)11]SP (KB, 0.03 nM); SR140333 but not SR48968, dose-dependently (IC50, 0.06 nM) antagonized the contractions elicited by capsaicin. In rat duodenum, containing mainly NK2 receptors, SR48968 caused a parallel rightward shift of the concentration-response curves of [beta-Ala8]NKA-(4-10) (pA2, 9.5), but not of NKA. In rat esophageal tunica muscularis mucosae, SR48968 non-competitively antagonized [beta-Ala8]NKA-(4-10) and NKA. SR48968 and SR140333 thus appear to be potent tachykinin receptor antagonists, selective for intestinal receptors respectively of the NK2 and NK1 type. The results also suggest that rat esophagus might contain a NK2-receptor subtype different from that of rat duodenum.
我们研究了强效非肽类速激肽受体拮抗剂SR140333和SR48968，观察它们预防非选择性激动剂P物质（SP）和神经激肽A（NKA），或分别为NK1和NK2受体选择性激动剂的[Sar9,Met(O2)11]SP和[β-Ala8]NKA-(4-10)引发的离体肠组织收缩的能力。在主要含NK1受体的豚鼠回肠中：SR140333对SP（平衡解离常数KB，0.01 nM）或[Sar9,Met(O2)11]SP（KB，0.03 nM）诱导的收缩产生假性不可逆阻断；SR140333而非SR48968剂量依赖性（半数抑制浓度IC50，0.06 nM）拮抗辣椒素引发的收缩。在主要含NK2受体的大鼠十二指肠中，SR48968使[β-Ala8]NKA-(4-10)（亲和力指数pA2，9.5）的浓度-反应曲线平行右移，但对NKA无此作用。在大鼠食管肌层黏膜中，SR48968对[β-Ala8]NKA-(4-10)和NKA产生非竞争性拮抗作用。因此，SR48968和SR140333似乎是强效速激肽受体拮抗剂，分别对NK2型和NK1型肠受体具有选择性。结果还提示，大鼠食管可能含有与大鼠十二指肠不同的NK2受体亚型。
