Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes.
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.
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000700:Analgesics; D000818:Animals; D001921:Brain / Q000201:enzymology; D004151:Dipeptides / Q000494:pharmacology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D010450:Endopeptidases; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D015260:Neprilysin; D011480:Protease Inhibitors; D011817:Rabbits; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology
D000700:Analgesics; D004151:Dipeptides; D004745:Enkephalins; D011480:Protease Inhibitors; C042591:kelatorphan; D004744:Enkephalin, Methionine; D015244:Thiorphan; D008625:Tiopronin; D010450:Endopeptidases; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III; D015260:Neprilysin; D007930:Leucine; C012211:ubenimex