title: Contribution of endopeptidase 3.4.24.15 to central neurotensin inactivation.
abstract: The tridecapeptide, neurotensin elicits naloxone-insensitive analgesia after its intracebroventricular administration in mice. We used this central pharmacological effect to assess the putative contribution of the endopeptidase 3.4.24.15 to central inactivation of the peptide. By means of combinatorial chemistry, we previously designed the first potent endopeptidase 3.4.24.15 inhibitor. This agent, Z-(L,D)Phe psi(PO2CH2)(L,D)Ala-Lys-Met (phosphodiepryl 21), is shown here to behave as a fully specific endopeptidase 3.4.24.15 inhibitor, as demonstrated by the absence of effect on a series of other exo- and endopeptidases belonging to various classes of proteolytic activities present in murine brain membranes. Furthermore, central administration of phosphodiepryl 21 drastically prolongs the forepaw licking latency of mice tested on the hot plate and injected with sub-maximally active doses of neurotensin. Altogether, our results demonstrated that, in addition to endopeptidase 3.4.24.16, endopeptidase 3.4.24.15 likely contributes to the physiological termination of the neurotensinergic message in murine brain.
authors.affiliation: Institut de pharmacologie moléculaire et Cellulaire 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; D000700:Analgesics; D000818:Animals; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D009496:Neurotensin; D009842:Oligopeptides / Q000494:pharmacology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C109926:phosphodiepryl 21; D009496:Neurotensin; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase