Larrivée J F, Gera L, Houle S, Bouthillier J, Bachvarov D R, Stewart J M, Marceau F
Centre Hospitalier Universitaire de Québec, Centre de recherche du Pavillon l'Hôtel-Dieu de Québec, Québec (Québec), Canada, G1R 2J6.
Br J Pharmacol. 2000 Nov;131(5):885-92. doi: 10.1038/sj.bjp.0703656.
The B(1) receptor for kinins, stimulated by kinin metabolites without the C-terminal Arg residue (e.g., des-Arg(9)-bradykinin (BK) and Lys-des-Arg(9)-BK), is an increasingly recognized molecular target for the development of analgesic and anti-inflammatory drugs. Recently developed antagonists of this receptor were compared to a conventional antagonist, Ac-Lys-[Leu(8)]-des-Arg(9)-BK, in pharmacological assays based on the rabbit B(1) receptor. B-9858 (Lys-Lys-[Hyp(3), Igl(5), D-Igl(7), Oic(8)]des-Arg(9)-BK) and three other analogues possessing the alpha-2-indanylglycine(5) (Igl(5)) residue (order of potency B-9858 approximately B-10146>B-10148>B-10050) were partially insurmountable antagonists of des-Arg(9)-BK in the contractility assay based on rabbit aortic rings. B-9858-induced depression of the maximal effect was more pronounced in tissues treated with the protein synthesis inhibitor cycloheximide to block the spontaneous increase of response attributed to the post-isolation formation of B(1) receptors, and only partly reversible on washing. By comparison, Ac-Lys-[Leu(8)]des-Arg(9)-BK was a surmountable antagonist (pA(2) 7. 5), even in cycloheximide-treated tissues. B-9958 (Lys-[Hyp(3), CpG(5), D-Tic(7), CpG(8)]des-Arg(9)-BK) was also surmountable (pA(2) 8.5). The binding of [(3)H]-Lys-des-Arg(9)-BK to recombinant rabbit B(1) receptors expressed in COS-1 cells was influenced by two of the antagonists: while Ac-Lys-[Leu(8)]des-Arg(9)-BK competed for the radioligand binding without affecting the B(max), B-9858 decreased the B(max) in a time-dependent and washout-resistant manner. B-9858 and analogues possessing Igl(5) are the first reported non-competitive, non-equilibrium antagonists of the kinin B(1) receptor.
激肽B(1)受体可被不含C末端精氨酸残基的激肽代谢产物（如去-Arg(9)-缓激肽（BK）和赖氨酸-去-Arg(9)-BK）激活，它日益成为镇痛药和抗炎药研发中备受关注的分子靶点。在基于兔B(1)受体的药理学试验中，将最近研发的该受体拮抗剂与传统拮抗剂Ac-Lys-[Leu(8)]-去-Arg(9)-BK进行了比较。B-9858（赖氨酸-赖氨酸-[Hyp(3)，Igl(5)，D-Igl(7)，Oic(8)]去-Arg(9)-BK）以及其他三种含有α-2-茚满甘氨酸(5)（Igl(5)）残基的类似物（效价顺序为B-9858≈B-10146>B-10148>B-10050）在基于兔主动脉环收缩性的试验中是去-Arg(9)-BK的部分不可逾越拮抗剂。在用蛋白质合成抑制剂环己酰亚胺处理以阻断因分离后B(1)受体形成导致的反应自发增加的组织中，B-9858引起的最大效应抑制更为明显，且冲洗后仅部分可逆。相比之下，即使在环己酰亚胺处理的组织中，Ac-Lys-[Leu(8)]去-Arg(9)-BK也是可逾越拮抗剂（pA(2) 7.5）。B-9958（赖氨酸-[Hyp(3)，CpG(5)，D-Tic(7)，CpG(8)]去-Arg(9)-BK）同样是可逾越拮抗剂（pA(2) 8.5）。[(3)H]-赖氨酸-去-Arg(9)-BK与COS-1细胞中表达的重组兔B(1)受体的结合受到两种拮抗剂的影响：Ac-Lys-[Leu(8)]去-Arg(9)-BK竞争放射性配体结合但不影响B(max)，而B-9858以时间依赖性和冲洗抗性方式降低B(max)。B-9858和含有Igl(5)的类似物是首次报道的激肽B(1)受体非竞争性、非平衡拮抗剂。
