title: Effect of a novel selective and potent phosphinic peptide inhibitor of endopeptidase 3.4.24.16 on neurotensin-induced analgesia and neuronal inactivation.
abstract: 1. We have examined a series of novel phosphinic peptides as putative potent and selective inhibitors of endopeptidase 3.4.24.16. 2. The most selective inhibitor, Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 displayed a Ki value of 12 nM towards endopeptidase 3.4.24.16 and was 5540 fold less potent on its related peptidase endopeptidase 3.4.24.15. Furthermore, this inhibitor was 12.5 less potent on angiotensin-converting enzyme and 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 neurotensin metabolism in the central nervous system was examined. 4. Pro-Phe-psi(PO2CHH2)-Leu-Pro-NH2 dose-dependently inhibited the formation of neurotensin 1-10 and concomittantly protected neurotensin from degradation by primary cultured neurones from mouse embryos. 5. Intracerebroventricular 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(PO2CH2)-Leu-Pro-NH2 as a fully selective and highly potent inhibitor of endopeptidase 3.4.24.16 and demonstrates, for the first time, the contribution of this enzyme in the central metabolism of neurotensin.
authors.affiliation: IPMC du CNRS, UPR411, Valbonne, France.
authors.forename: B
authors.initials: B
authors.lastname: Vincent
authors.forename: J
authors.initials: J
authors.lastname: Jiracek
authors.forename: F
authors.initials: F
authors.lastname: Noble
authors.forename: M
authors.initials: M
authors.lastname: Loog
authors.forename: B
authors.initials: B
authors.lastname: Roques
authors.forename: V
authors.initials: V
authors.lastname: Dive
authors.forename: J P
authors.initials: JP
authors.lastname: Vincent
authors.forename: F
authors.initials: F
authors.lastname: Checler
mesh_terms: D000698:Analgesia; D000818:Animals; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D009496:Neurotensin / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010720:Phosphines / Q000494:pharmacology*; D051381:Rats
chemical_list: D009842:Oligopeptides; D010720:Phosphines; C108037:prolyl-phenylalanyl-psi(PO2CH2)-leucyl-prolinamide; D009496:Neurotensin; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases; C062316:neurolysin