Fournié-Zaluski M C, Soroca-Lucas E, Waksman G, Llorens C, Schwartz J C, Roques B P
Life Sci. 1982 Dec 27;31(26):2947-54. doi: 10.1016/0024-3205(82)90060-1.
New carboxylalkyl compounds derived from Phe-Leu and corresponding to the general formula C6H5-CH2-CH(R)CO-L.Leu with R = -COOH, 3, R = -CH2-COOH, 4, R = -NH-CH2-COOH, 5, R = -NH-(CH2)2-COOH, 6, have been found to inhibit the breakdown of the Gly3-Phe4 bond of [3H] Leu-enkephalin or [3H]D.Ala2-Leu-enkephalin resulting from the action of the mouse striatal metallopeptidases: "enkephalinase" or angiotensin-converting enzyme (A.C.E.). The carboxyl coordinating ability of the Zn atom seems to be significantly higher in ACE than in "enkephalinase". Moreover, IC50 values against "enkephalinase" were found in the same range whatever the length of the chain bearing the carboxyl group whereas a well-defined position of this group with respect to the Zn atom is required for strong ACE inhibition. These features suggest a larger degree of freedom of the carboxyalkyl moieties within the active site of "enkephalinase". Therefore the differential recognition of active sites of both peptidases leads to: i) N-(carboxymethyl)-L-Phe-L-Leu, 5, a competitive inhibitor of "enkephalinase" (KI = 0.7 microM) and ACE (KI = 1.2 microM) which could be used as mixed inhibitor for both enzymes; ii) N-[(R,S)-2-carboxy, 3-benzylpropanoyl]-L-Leucine, 3, a full competitive inhibitor of "enkephalinase" (KI = 0.34 microM) which does not interact with ACE (IC50 greater than 10,000 microM). This compound can be considered as the first example of a new series of highly potent and specific "enkephalinase" inhibitors.
已发现源自苯丙氨酸 - 亮氨酸且对应通式为C6H5 - CH2 - CH(R)CO - L.Leu的新型羧基烷基化合物，其中R = -COOH（化合物3）、R = -CH2 - COOH（化合物4）、R = -NH - CH2 - COOH（化合物5）、R = -NH - (CH2)2 - COOH（化合物6），可抑制小鼠纹状体金属肽酶“脑啡肽酶”或血管紧张素转换酶（A.C.E.）作用导致的[3H]亮氨酸脑啡肽或[3H]D - Ala2 - 亮氨酸脑啡肽中Gly3 - Phe4键的断裂。锌原子的羧基配位能力在ACE中似乎比在“脑啡肽酶”中显著更高。此外，无论带有羧基的链长度如何，针对“脑啡肽酶”的IC50值都在相同范围内，而对于强烈抑制ACE而言，该基团相对于锌原子需要有明确的位置。这些特征表明“脑啡肽酶”活性位点内羧基烷基部分具有更大的自由度。因此，对两种肽酶活性位点的差异识别导致：i）N - （羧甲基） - L - 苯丙氨酸 - L - 亮氨酸（化合物5），它是“脑啡肽酶”（KI = 0.7 microM）和ACE（KI = 1.2 microM）的竞争性抑制剂，可作为两种酶的混合抑制剂；ii）N - [（R，S） - 2 - 羧基，3 - 苄基丙酰基] - L - 亮氨酸（化合物3），它是“脑啡肽酶”的完全竞争性抑制剂（KI = 0.34 microM），不与ACE相互作用（IC50大于10,000 microM）。该化合物可被视为一系列新型高效且特异性“脑啡肽酶”抑制剂中的首个实例。
