SELECTIVE-INHIBITION OF THROMBIN BY (2R,4R)-4-METHYL-1-[N2-[(3-METHYL-1,2,3,4-TETRAHYDRO-8-QUINOLINYL)SULFONYL]-L-ARGINYL)]-2-PIPERIDINECARBOXYLIC ACID
SELECTIVE-INHIBITION OF THROMBIN BY (2R,4R)-4-METHYL-1-[N2-[(3-METHYL-1,2,3,4-TETRAHYDRO-8-QUINOLINYL)SULFONYL]-L-ARGINYL)]-2-PIPERIDINECARBOXYLIC ACID
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DOI：
10.1021/bi00296a014
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发表时间：
1984-01-01
期刊：
影响因子：
2.9
通讯作者：
OKAMOTO, S
中科院分区：
文献类型：
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作者：
KIKUMOTO, R;TAMAO, Y;OKAMOTO, S
4-甲基-1-[N2-[（3-甲基-1，2，3，4-四氢-8-喹啉基）磺酰基]-L-乙酰基]-2-哌啶羧酸（MQPA）抑制[人]凝血酶的效力取决于2-哌啶羧酸部分的立体构象。牛α的Ki值凝血酶与（2 R，4 R）-MQPA的浓度为0.019 μ M，与（2 R，4S）-MQPA的浓度为0.24 μ M，与（2S，4 R）-MQPA的浓度为1.9 μ M，与（2S，4S）-MQPA的浓度为280 μ M。(2R MQPA的4种立体异构体中的（4 R）-MQPA也是其它胰蛋白酶样丝氨酸蛋白酶的最有效的抑制剂，其Ki值对于胰蛋白酶为5.0 μ M，对于因子Xa为210 μ M，对于纤溶酶为800 μ M，对于血浆激肽释放酶为1500 μ M。在结构上与MQPA相关的精氨酸衍生物对凝血酶抑制效力的检查表明存在羧酰胺部分（C-末端侧）的特异性结合位点。MQPA的4种立体异构体对胰蛋白酶的相对抑制效力与对凝血酶的相对抑制效力几乎相同，表明羧酰胺部分的特异性结合位点存在于两种酶中。通过磷酸化或肝素的存在对凝血酶进行修饰并没有显著改变MQPA的结合。
The potency of [human] thrombin inhibition by 4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidinecarboxylic acid (MQPA) depended on the stereoconformation of the 2-piperidine-carboxylic acid moiety. Ki values for bovine .alpha.-thrombin were 0.019 .mu.M with (2R,4R)-MQPA, 0.24 .mu.M with (2R,4S)-MQPA, 1.9 .mu.M with (2S,4R)-MQPA and 280 .mu.M with (2S,4S)-MQPA. (2R,4R)-MQPA of the 4 stereoisomers of MQPA was also the most potent inhibitor for other trypsin-like serine proteases with Ki values of 5.0 .mu.M for trypsin, 210 .mu.M for factor Xa, 800 .mu.M for plasmin and 1500 .mu.M for plasma kallikrein. Examination of the potency of thrombin inhibition by arginine derivatives related to MQPA in structure suggested the presence of a specific binding site for the carboxamide portion (C-terminal side). The relative inhibitory potency of the 4 stereoisomers of MQPA for trypsin was nearly identical with that for thrombin, suggesting that the specific binding site for the carboxamide portion is present in both enzymes. Modification of thrombin by phosphopyridoxylation or the presence of heparin did not significantly alter the binding of MQPA.