Giros B, Gros C, Schwartz J C, Danvy D, Plaquevent J C, Duhamel L, Duhamel P, Vlaiculescu A, Costentin J, Lecomte J M
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l'Institut National de la Santé et de la Recherche Médicale, Paris, France.
J Pharmacol Exp Ther. 1987 Nov;243(2):666-73.
The relationships between various properties of inhibitors of enkephalinase (membrane metalloendopeptidase, EC 3.4.24.11) i.e., enzyme inhibition, protection of endogenous enkephalins, antinociceptive activity and stimulation of locomotor activity was investigated by comparing the relative potencies of the two enantiomers of Thiorphan and acetorphan, its parenterally active prodrug. In vitro (R)- and (S)-Thiorphan were almost equipotent in inhibiting enkephalinase activity (Ki, 1.7 and 2.2 nM, respectively) or thermolysin activity (Ki, 13 and 6 microM, respectively) whereas the (R)-isomer was 44-fold less potent than the (S)-isomer on ACE activity (Ki 4800 and 110 nM, respectively). When tested on slices of rat globus pallidus in the presence of bestatin, to block the aminopeptidase pathway of enkephalin degradation, both Thiorphan enantiomers ensured a complete protection of endogenous (Met5)enkephalin released by depolarization and a suppression of the increase in the extracellular levels of Tyr-Gly-Gly, a characteristic enkephalin metabolite. These two effects occurred at EC50 values of the two enantiomers (10 nM in both cases), consistent with the idea that they were due to enkephalinase inhibition. After i.v. administration of the acetorphan enantiomers to mice, the enkephalinase activity of a rapidly prepared striatal membrane fraction was reduced in a dose-dependent manner with similar "ex vivo" ED50 values (1.0 and 0.3 mg/kg for the (R)- and (S)-isomer, respectively). In contrast the ACE activity of the same preparation was reduced in a significant manner only by (S)-acetorphan (ED50 value of 11 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
通过比较硫喷妥和阿醋芬（其肠道外活性前体药物）两种对映体的相对效力，研究了脑啡肽酶（膜金属内肽酶，EC 3.4.24.11）抑制剂的各种性质之间的关系，即酶抑制、内源性脑啡肽的保护、抗伤害感受活性和运动活性刺激。在体外，（R）-和（S）-硫喷妥在抑制脑啡肽酶活性（Ki分别为1.7和2.2 nM）或嗜热菌蛋白酶活性（Ki分别为13和6 μM）方面几乎效力相当，而（R）-异构体在ACE活性上比（S）-异构体效力低44倍（Ki分别为4800和110 nM）。在存在贝司他汀的情况下对大鼠苍白球切片进行测试，以阻断脑啡肽降解的氨肽酶途径时，两种硫喷妥对映体都能确保完全保护去极化释放的内源性（Met5）脑啡肽，并抑制脑啡肽特征性代谢产物Tyr-Gly-Gly细胞外水平的升高。这两种作用在两种对映体的EC50值（两种情况下均为10 nM）时出现，这与它们是由于脑啡肽酶抑制的观点一致。给小鼠静脉注射阿醋芬对映体后，快速制备的纹状体膜部分的脑啡肽酶活性以剂量依赖性方式降低，“离体”ED50值相似（（R）-和（S）-异构体分别为1.0和0.3 mg/kg）。相反，同一制剂的ACE活性仅被（S）-阿醋芬显著降低（ED50值为11 mg/kg）。（摘要截断于250字）
