Protection of enkephalins from enzymatic degradation utilizing selective metal-chelating inhibitors.
Metal ion-chelating agents inhibited enkephalin degradation by a rat striatal membrane-associated endopeptidase termed 'enkephalinase'. The combination of a hydrophobic dipeptidyl moiety and a transition metal-chelating moiety in the same molecule resulted in very efficient and selective inhibitors of enkephalinase. The mercaptoacetyl dipeptides (2-mercaptoacetyl-Leu-Phe and 2-mercaptoacetyl-Phe-Leu) and the N-phosphorylated dipeptides (phosphoryl-Leu-Phe and phosphoramidon) inhibited enkephalinase with IC50 values of 15, 70, 0.3 and 1 nM respectively, but were much less potent against the aminopeptidase and angiotensin converting enzyme, two other metalloenzymes implicated in the degradation of the enkephalins in brain. The inhibition of enkephalinase, using phosphoryl-Leu-Phe as a selective inhibitor, resulted in a 4 fold increase in the amount of enkephalin recovered following K+ depolarization of rat striatal slices.
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism*; D066298:In Vitro Techniques; D015260:Neprilysin; D011480:Protease Inhibitors; D051381:Rats
D002614:Chelating Agents; D004745:Enkephalins; D011480:Protease Inhibitors; D004743:Enkephalin, Leucine; D000626:Aminopeptidases; D015260:Neprilysin