HYPOALGESIC ACTION OF BESTATIN ANALOGS THAT INHIBIT CENTRAL AMINOPEPTIDASES, BUT NOT NEUTRAL ENDOPEPTIDASE

Two analogues of the aminopeptidase inhibitor bestatin, Z 4212 (N-[(2S , phenyl)-1-oxobutyl]-1-aminocyclopentanecarboxylic) and Z 1796 4-(4-m ethylsulphonylphenyl)-1-oxobutyl]-L-leucine) were found to behave as h ypoalgesics when intracerebroventricularly (i.c.v.) administered to mi ce in the hot-plate test. At high doses, Z 4212 was also found to redu ce the pain threshold after intraventricular (i.v.) administration. Hy poalgesia induced by bestatin analogues was prevented by prior treatme nt with the opiate receptor blocker naloxone. Thiorphan, a potent inhi bitor of NEP was found to enhance the hypoalgesic effect of low doses of either Z 4212 or Z 1796. These results indicate that both the major opioid-degrading peptidases, i.e. aminopeptidases and neutral endopep tidase (NEP), are individually implicated in the hypoalgesia induced b y peptidase inhibitors. In vitro studies showed that these new bestati n analogues readily inhibit aminopeptidases in membranes from mouse c. striatum whereas more than 1000 times the concentration was required for NEP to be blocked. Ex vivo experiments showed that, at variance wi th bestatin, the hypoalgesic action of Z 4212 or Z 1796 appeared to im plicate central aminopeptidases but not NEP, so partially sparing the metabolism of other NEP substrates that might produce additional alter ations (substance P and ANP). On the basis of the antitumour and immun omodulatory actions of bestatin, these new analogues might be potentia lly useful as mixed antitumour and hypoalgesic agents in malignancy.