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Kelatorphan, [(R)-3-(N-hydroxy)-carboxamido-2-benzylpropanoyl]-L-alanine, represents the first virtually complete inhibitor of enkephalins metabolism with KI = 1.4 nM against enkephalinase, KI = 2 nM against the Gly2 -Gly3 cleaving dipeptidylaminopeptidase and KI = 7 microM on aminopeptidase activity. The analgesic effect of [Met5]enkephalin was potentiated(More)
Biologically relevant assays were used to compare the potency of kelatorphan (N-[3(R)-[(hydroxyamino)carbonyl]-2-benzyl-1-oxopropyl]-L-alanine) as inhibitor of the peptidase-induced metabolism of enkephalins to that of bestatin, a non-specific inhibitor of aminopeptidase and thiorphan, a highly potent blocker of the neutral endopeptidase (EC 3.4.24.11)(More)
The effects of the novel mixed peptidase inhibitor, kelatorphan [N-(R)-3-(N-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl)-L-alanine], were compared to those of a combination of the potent "enkephalinase" inhibitor thiorphan and the nonselective aminopeptidase inhibitor bestatin, on the catabolism of [3H]Met-enkephalin and on the release of endogenous(More)
Three series of bidentates bearing an hydroxamic or an N-Acyl-N-hydroxy amino group on structures related to Phe-Gly or Phe-Ala exhibit strong inhibitory potency against purified enkephalinase with IC50 values in the 4 to 15 nM range. As with thiol-containing inhibitors, such as thiorphan, the most active compounds are those in which a methylene spacer(More)
Sequence-based inhibitors of collagenase bearing an hydroxamate group capable of chelating the active site zinc atom were synthesized and tested. The effect of one of these molecules (RP 59794; Ki about 10(-8) M) on the formation of the TIMP: collagenase complex was also tested. RP 59794 blocks complex formation and can partially dissociate established(More)
New compounds were designed to fully inhibit the in vitro metabolism of enkephalins, ensured by three different metallopeptidases. For this purpose, bidentate ligands as hydroxamate and N-hydroxy-N-formylamino groups were selected as highly potent metal coordinating agents and introduced on Phe-Gly and Phe-Ala related structures. Compounds corresponding to(More)
The synthesis and binding properties to rat brain tissue of the enkephalinase inhibitor [3H] N-[(R,S)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]-glycine ([3H]HACBO-Gly, 45 Ci/mmole) is reported. [3H]HACBO-Gly binding to membranes from various rat brain tissue is saturable (KD = 0.4 +/- 0.05 nM) and linearly related to the amount of tissue. Non specific(More)
Actinonin is a pseudopeptide antibiotic which inhibits collagenase at micromolar concentrations [10]. In this study, Actinonin analogs were tested to investigate "structure/activity" relationships for this class of molecule. The results indicate that distance between the hydroxamate carbonyl group and that of the first amide bond is important, since(More)
New potent inhibitors of enkephalin degrading enzymes were obtained by synthesis of compounds bearing a bidentate group. Among these bidentates, Kelatorphan, N-[(R)-3-(N-hydroxy)-carboxamido-2-benzylpropanoyl]-L-alanine, is in vitro a full inhibitor of enkephalinase, dipeptidylaminopeptidase and aminopeptidase. In vivo Kelatorphan (i.c.v. administered in(More)
The first visualization of enkephalinase (neutral metalloendopeptidase, E.C.3.4.24.11) in rat brain was obtained by autoradiography, using a new tritiated inhibitor: [3H]N-[( R,S )3-(N-hydroxy) carboxamido-2-benzyl propanoyl]glycine (3H-HCBP-Gly). The preliminary analysis of sections clearly showed a discrete localization of enkephalinase in enkephalin(More)
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