Cirillo R, Astolfi M, Conte B, Lopez G, Parlani M, Terracciano R, Fincham C I, Manzini S
Pharmacology Department, Menarini Ricerche, Pomezia, Italy.
Eur J Pharmacol. 1998 Jan 12;341(2-3):201-9. doi: 10.1016/s0014-2999(97)01453-2.
In this study we investigated the pharmacological properties of MEN 11149, 2-(2-naphthyl)-1-N-[(1R,2S)-2-N-[1(H)indol-3-ylcarbonyl]aminocy clohexanecarbonyl]-1-[N'-methyl-N'-(4-methylphenylacetyl)]di aminoethane, a novel partially retro-inverse pseudo peptide antagonist of tachykinin NK1 receptors. MEN 11149 potently inhibits the binding of [3H]substance P to tachykinin NK1 sites in IM9 cells (pKi = 8.5 +/- 0.1). The compound is highly specific for the human tachykinin NK1 receptors, since it has negligible effects (pKi < 6) on the binding of specific ligands to tachykinin NK2, NK3 receptors and a battery of central and peripheral receptors or ion channels. The tachykinin NK1 receptor antagonism of MEN 11149 appears to be insurmountable since, in saturation binding experiments, both K(D) and Bmax are significantly affected by incubation with the compound (1-30 nM). In isolated guinea-pig ileum, MEN 11149 (0.1-100 nM) shifts to the right in a non-parallel way the substance P methyl ester-induced cumulative concentration-response curve with progressive inhibition of the maximal response (pK(B) = 9.6 +/- 0.1). When tested for reversibility at 5 nM in the same preparation, the compound displays a slow dissociation rate compared to the fast dissociation rate with FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)alaninamide) at 5 nM. In the same preparation, MEN 11149 (10 microM) did not affect the cumulative concentration-response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes [Sar9,Met(O2)11]substance P-induced bronchoconstriction in anaesthetized guinea-pigs (ID50 = 83 +/- 31 nmol/kg i.v.). The duration of the effect exceeds 3 h. MEN 11149 does not affect the bronchoconstriction induced by neurokinin A. The compound dose dependently inhibits [Sar9,Met(O2)11]substance P-induced plasma protein extravasation in guinea-pig bronchi whether administered intravenously (ID50 = 0.22 +/- 0.02 micromol/kg) or orally (ID50 = 0.97 +/- 0.21 micromol/kg). These results demonstrate that MEN 11149 is a potent, highly selective and orally effective insurmountable antagonist of tachykinin NK1 receptors with a long duration of action.
在本研究中，我们研究了MEN 11149（2-(2-萘基)-1-N-[(1R,2S)-2-N-[1(H)-吲哚-3-基羰基]氨基环己烷羰基]-1-[N'-甲基-N'-(4-甲基苯乙酰基)]二氨基乙烷）的药理学特性，它是一种新型的速激肽NK1受体部分反向拟肽拮抗剂。MEN 11149能有效抑制[3H]P物质与IM9细胞中速激肽NK1位点的结合（pKi = 8.5±0.1）。该化合物对人速激肽NK1受体具有高度特异性，因为它对特异性配体与速激肽NK2、NK3受体以及一系列中枢和外周受体或离子通道的结合影响可忽略不计（pKi < 6）。MEN 11149对速激肽NK1受体的拮抗作用似乎是不可克服的，因为在饱和结合实验中，K(D)和Bmax均受到与该化合物（1 - 30 nM）孵育的显著影响。在离体豚鼠回肠中，MEN 11149（0.1 - 100 nM）以非平行方式使P物质甲酯诱导的累积浓度 - 反应曲线右移，同时对最大反应进行渐进性抑制（pK(B) = 9.6±0.1）。当在同一制剂中以5 nM测试其可逆性时，与5 nM的FK888（N2-[(4R)-4-羟基-1-(1-甲基-1H-吲哚-3-基)羰基-L-脯氨酰]-N-甲基-N-苯甲基-L-3-(2-萘基)丙氨酰胺）相比，该化合物显示出较慢的解离速率。在同一制剂中，MEN 11149（10 μM）不影响对乙酰胆碱的累积浓度 - 反应曲线。在体内，MEN 11149剂量依赖性地拮抗[Sar9,Met(O2)11]P物质在麻醉豚鼠中诱导的支气管收缩（静脉注射ID50 = 83±31 nmol/kg）。作用持续时间超过3小时。MEN 11149不影响神经激肽A诱导的支气管收缩。该化合物剂量依赖性地抑制[Sar9,Met(O2)11]P物质在豚鼠支气管中诱导的血浆蛋白外渗，无论是静脉注射（ID50 = 0.22±0.02 μmol/kg）还是口服（ID50 = 0.97±0.21 μmol/kg）。这些结果表明，MEN 11149是一种强效、高度选择性且口服有效的速激肽NK1受体不可克服的拮抗剂，作用持续时间长。
