EFFECT OF A NOVEL SELECTIVE AND POTENT PHOSPHINIC PEPTIDE INHIBITOR OF ENDOPEPTIDASE-3.4.24.16 ON NEUROTENSIN-INDUCED ANALGESIA AND NEURONAL INACTIVATION

1 We have examined a series of novel phosphinic peptides as putative p otent and selective inhibitors of endopeptidase 3.4.24.16. 2 The most selective inhibitor, Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 displayed a K-i v alue of 12 nM towards endopeptidase 3.4.24.16 and was 5540 fold less p otent on its related peptidase endopeptidase 3.4.24.15. Furthermore, t his inhibitor was 12.5 less potent on angiotensin-converting enzyme an d was unable to block endopeptidase 3.4.24.11, aminopeptidases B and M , dipeptidylaminopeptidase IV and proline endopeptidase. 3 The effect of Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2, in vitro and in vivo, on neurotens in metabolism in the central nervous system was examined. 4 Pro-Phe-ps i(PO2CHH2)-Leu-Pro-NH2 dose-dependently inhibited the formation of neu rotensin 1-10 and concomitantly protected neurotensin from degradation by primary cultured neurones from mouse embryos. 5 Intracerebroventri cular administration of Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 significantly potentiated the neurotensin-induced antinociception of mice in the hot plate test. 6 Altogether, our study has established Pro-Phe-psi(PO2CH 2)-Leu-Pro-NH2 as a fully selective and highly potent inhibitor of end opeptidase 3.4.24.16 and demonstrates, for the first time, the contrib ution of this enzyme in the central metabolism of neurotensin.