Abstract
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 50000 times (ED50 approximately 10 ng) by intracerebroventricular co-administration in mice of kelatorphan (50 micrograms). This effect was significantly higher than that produced by bestatin (50 micrograms) + thiorphan (50 micrograms). Kelatorphan alone was at least two-fold more potent as analgesic than the above mixture of inhibitors.
MeSH terms
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Aminopeptidases / antagonists & inhibitors
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Analgesics*
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Animals
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Brain / enzymology
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Dipeptides / pharmacology*
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
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Endopeptidases
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Enkephalin, Methionine / pharmacology
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Enkephalins / metabolism*
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In Vitro Techniques
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Kidney / enzymology
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Leucine / analogs & derivatives
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Leucine / pharmacology
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Neprilysin
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Protease Inhibitors
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Rabbits
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Rats
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Reaction Time / drug effects
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Thiorphan
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Tiopronin / analogs & derivatives
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Tiopronin / pharmacology
Substances
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Analgesics
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Dipeptides
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Enkephalins
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Protease Inhibitors
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kelatorphan
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Enkephalin, Methionine
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Thiorphan
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Tiopronin
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Endopeptidases
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Aminopeptidases
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enkephalin degrading enzyme
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
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dipeptidyl peptidase III
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Neprilysin
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Leucine
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ubenimex