SYNTHESIS AND ANALGESIC EFFECTS OF L]-1-OXO-2(R)-BENZYLPROPYL]-L-ISOLEUCYL-L-LEUCINE, A NEW POTENT INHIBITOR OF MULTIPLE NEUROTENSIN NEUROMEDIN-N DEGRADING ENZYMES

The synthesis of yl]-1-oxo-2(R)-benzylpropyl]-L-isoleucyl-L-leucine (J MV-390-1, 6a), a multipeptidase inhibitor based on the C-terminal sequ ence common to neurotensin (NT) and neuromedin N (NN), is described. T his compound behaves as a full inhibitor of the major NT/NN degrading enzymes in vitro, e.g. endopeptidase 24.16, endopeptidase 24.15, endop eptidase 24.11, and leucine aminopeptidase (type IV-S), in the nanomol ar range (IC50's from 30 to 60 nM). Compound 6a was found to increase endogenous recovery of NT and NN from slices of mice hypothalamus depo larized with potassium. In various assays commonly used to select anal gesics, e.g. hot-plate test, tail-flick test, acetic acid-induced writ hing test, in mice, compound 6a proved to be potent when intracerebrov entricularly (icv) injected. The analgesic effects observed were total ly (hot-plate test) or largely (tail-flick test) reversed by the opioi d antagonist naltrexone. Furthermore, icv injection of compound 6a (10 mug/mouse) was found to significantly potentiate the hypothermic effe cts of NT or NN.