[Enkephalinase inhibitors and molecular study of the differences between active sites of enkephalinase and angiotensin-converting enzyme].
With the aim of producing an analgesia physiologically induced by endogenous opioids, several series of inhibitors of the degradation enzymes of enkephalins have been synthetized by using as a model, at the atomic level, the active site of thermolysin, a bacterial endopeptidase similar to enkephalinase. Thiorphan and retro-thiorphan are very potent inhibitors of enkephalinase (KI = 2 nM), but the retro compound is more selective, as it is unable to recognise the angiotensin conversion enzyme. Recently, a series of inhibitors containing a bidentate group were found to be capable of inhibiting the three metallopeptidases which break down the enkephalins. One of these compounds, kelatorphan, totally protects, in vitro and in vivo, Met-enkephalin from enzymatic degradation. Kelatorphan is the first complete inhibitor of enkephalin metabolism and is the only compound to possess an analgesic activity greater than that of a mixture of thiorphan and bestatin (non-specific aminopeptidase inhibitor). A tritiated derivative of kelatorphan has been used to visualise the enkephalinase in the rat brain by means of autoradiography. The enzyme has a heterogeneous distribution with a particularly high concentration in the nigro-striatal system.
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D000700:Analgesics; D000818:Animals; D001665:Binding Sites; D004357:Drug Synergism; D010450:Endopeptidases / Q000032:analysis / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008666:Metalloendopeptidases; D015260:Neprilysin; D007703:Peptidyl-Dipeptidase A / Q000032:analysis*; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology
D000700:Analgesics; D004745:Enkephalins; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D015244:Thiorphan; D008625:Tiopronin; D010450:Endopeptidases; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases; D015260:Neprilysin
Inhibiteurs d'enképhalinase et exploration moléculaire des différences entre sites actifs de l'enképhalinase et de l'enzyme de conversion de l'angiotensine.