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.