Article date: June 1997
By: Bruno Vincent, Jirì Jiracek, Florence Noble, Mart Loog, Bernard Roques, Vincent Dive, Jean‐Pierre Vincent, Frédéric Checler, in Volume 121, Issue 4, pages 705-710
We have examined a series of novel phosphinic peptides as putative potent and selective inhibitors of endopeptidase 3.4.24.16.
The most selective inhibitor, Pro‐Phe‐Ψ(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.
The effect of Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2, in vitro and in vivo, on neurotensin metabolism in the central nervous system was examined.
Pro‐Phe‐Ψ(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.
Intracerebroventricular administration of Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2 significantly potentiated the neurotensin‐induced antinociception of mice in the hot plate test.
Altogether, our study has established Pro‐Phe‐Ψ(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.
We have examined a series of novel phosphinic peptides as putative potent and selective inhibitors of endopeptidase 3.4.24.16.
The most selective inhibitor, Pro‐Phe‐Ψ(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.
The effect of Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2, in vitro and in vivo, on neurotensin metabolism in the central nervous system was examined.
Pro‐Phe‐Ψ(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.
Intracerebroventricular administration of Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2 significantly potentiated the neurotensin‐induced antinociception of mice in the hot plate test.
Altogether, our study has established Pro‐Phe‐Ψ(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.
British Journal of Pharmacology (1997) 121, 705–710; doi:10.1038/sj.bjp.0701182
DOI: 10.1038/sj.bjp.0701182
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