Rhaleb N E, Rouissi N, Jukic D, Regoli D, Henke S, Breipohl G, Knolle J
University of Sherbrooke, Quebec, Canada.
Eur J Pharmacol. 1992 Jan 14;210(2):115-20. doi: 10.1016/0014-2999(92)90661-m.
HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a new B2 antagonist, was compared to R-493 (D-Arg[Hyp3-D-Phe7,Leu8]bradykinin) with respect to inhibition of the responses of seven isolated smooth muscle preparations to bradykinin. R-493 was found to exert: (a) high antagonistic activity on the rabbit jugular vein (pA2 of 8.86), (b) moderate activity on the rabbit aorta, guinea-pig ileum, hamster urinary bladder and human urinary bladder (pA2 of 5.76, 6.77, 7.16 and 7.15, respectively) and (c) a stimulatory effect on the guinea-pig trachea. On the other hand, HOE 140 showed identical apparent affinities (8.36-9.12) on all preparations except the rabbit aorta where it was inactive and the guinea-pig trachea where the compound was an antagonist (pA2: 7.42) without agonistic effect. HOE 140 is specific and selective for B2 receptors since it was inactive against angiotensin II, substance P, neurokinin A, desArg9-bradykinin, noradrenaline or acetylcholine in the various preparations. R-493 inhibited the contractile effects of bradykinin competitively, while HOE 140 was not competitive even at low concentrations (7.7 x 10(-9) M). These results demonstrate that HOE 140 is a potent B2 antagonist with high affinity, specific for kinin receptors and selective for the B2 receptor type, but is non-competitive. HOE 140 is the first bradykinin receptor antagonist that acts as such on the guinea-pig trachea without showing any agonistic activity.
将新型B2拮抗剂HOE 140（D-精氨酸-[Hyp3,Thi5,D- Tic7,Oic8]缓激肽）与R-493（D-精氨酸[Hyp3-D-苯丙氨酸7,亮氨酸8]缓激肽）就抑制七种离体平滑肌制剂对缓激肽的反应进行了比较。发现R-493具有：(a) 对兔颈静脉有高拮抗活性（pA2为8.86），(b) 对兔主动脉、豚鼠回肠、仓鼠膀胱和人膀胱有中等活性（pA2分别为5.76、6.77、7.16和7.15），以及(c) 对豚鼠气管有刺激作用。另一方面，HOE 140在除兔主动脉（无活性）和豚鼠气管（该化合物为拮抗剂，pA2：7.42，无激动作用）外的所有制剂上显示出相同的表观亲和力（8.36 - 9.12）。HOE 140对B2受体具有特异性和选择性，因为它在各种制剂中对血管紧张素II、P物质、神经激肽A、去精氨酸9-缓激肽、去甲肾上腺素或乙酰胆碱无活性。R-493竞争性抑制缓激肽的收缩作用，而HOE 140即使在低浓度（7.7×10(-9)M）时也无竞争性。这些结果表明，HOE 140是一种强效的B2拮抗剂，具有高亲和力，对激肽受体具有特异性，对B2受体类型具有选择性，但无竞争性。HOE 140是第一个在豚鼠气管上如此作用而不显示任何激动活性的缓激肽受体拮抗剂。
