CONTRIBUTION OF ENDOPEPTIDASE 3.4.24.15 TO CENTRAL NEUROTENSIN INACTIVATION

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 po tent endopeptidase 3.4.24.15 inhibitor. This agent, Z-(L,D)Phe Psi(PO2 CH2)(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 bel onging 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 neurote nsin. Altogether, our results demonstrated that, in addition to endope ptidase 3.4.24.16, endopeptidase 3.4.24.15 likely contributes to the p hysiological termination of the neurotensinergic message in murine bra in. (C) 1997 Elsevier Science B.V.