Design and evaluation of inhibitors of enkephalin degrading enzymes

The endogenous opioid peptides enkephalins are degraded in vitro by several metallopeptidases (aminopeptidases, enkephalinase, dipeptidylaminopeptidases). Selective and mixed inhibitors of these enzymes were obtained by a rational approach taking into account crystallographic data on Thermolysin, a bacterial enzyme, used as model of metallopeptidase active site. This strategy is supported by recent cloning of enkephalinase. As expected, a physiological analgesia is produced by administration of inhibitors, especially kelatorphan and analogues, demonstrating unambiguously the implication of enkephalinase and aminopeptidase M in enkephalin metabolism. The intensive studies on endogenous opioid system have shown that inhibitors of enkephalin metabolism represent very useful probes and promising new analgesics.