Opioid peptides such as the enkephalins are known to act as neurotransmitters and neuromodulators. The action of these peptides is terminated by peptide cleavage into inactive products. Strong evidence has been presented by numerous investigators for the role of an """"""""enkephalinase"""""""" (neutral endopeptidase 24.11) in the termination of enkephalin action. This evidence consists of, among other things, the localization of enkephalinase to nerve terminals as well as inducement of analgesia upon introduction of enkephalinase inhibitors. This analgesic effect produced by enkephalinase inhibitors offers the possibility of opiate strength pain relief with a minimum of side effects such as dependence and tolerance. These inhibitors may also be of assistance in alleviating many alkaloid opiate withdrawal symptoms. To design more specific and potent enkephalinase inhibitors, this proposal describes a mechanism-based approach. Design of potential inhibitors will be based on the ability of the enkephalinase active site to either abstract a proton from or donate a proton to a substrate analog, thereby generating a reactive chemical group which will inactivate the enzyme. The designed compounds will be synthesized and tested against the purified enzyme. Inhibitors generated in this manner will represent the first enzyme-activated (mechanism-based) irreversible inhibitors of a metallopeptidase and should be potent analgesics.
