Synthesis of enkephalinase B inhibitors, and their activity on isolated enkephalin-degrading enzymes.
Compounds in which a dipeptide moiety is linked to a metal chelating mercapto group were synthesized to obtain effective enkephalinase B inhibitors. Inhibitors containing two hydrophobic amino acid side-chains decrease enkephalinase B activity with a potency depending on the length of the spacer connecting the mercapto group and the dipeptide (IC50 values vary between 0.35 and 14 microM) and they also inhibit enkephalinase A and aminopeptidase activity. Compounds lacking the carboxy terminal side-chain are not recognized by enkephalinase B or aminopeptidase but are potent inhibitors of enkephalinase A. Our most potent enkephalinase B inhibitor is mercaptoacetyl-Phe-Phe (designated phelorphan), having an IC50 value of 0.35 microM for enkephalinase B. This compound also effectively inhibits enkephalinase A (IC50 = 0.02 microM) and aminopeptidase activity (IC50 = 13 microM). Phelorphan can therefore be considered as a complete inhibitor of enkephalin biodegradation.
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000378:metabolism; D010450:Endopeptidases; D004745:Enkephalins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D015260:Neprilysin; D011480:Protease Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D002614:Chelating Agents; D004151:Dipeptides; D004745:Enkephalins; D011480:Protease Inhibitors; C053652:phelorphan; D010450:Endopeptidases; D015260:Neprilysin