Reduced peptide bond pseudopeptide analogues of neurotensin.
Pseudopeptide analogues of the C-terminal hexapeptide of neurotensin (H-Arg-Arg-Pro-Tyr-Ile-Leu-OH) were obtained by replacing each peptide bond by the reduced peptide bond CH2NH. The resulting analogues were then examined for their ability to inhibit binding of labeled neurotensin to new-born mouse brain membranes and for stimulation of guinea pig ileum contraction. Replacement of the Ile12-Leu13, Tyr11-Ile12, Pro10-Tyr11 and Lys9-Pro10 peptide bonds resulted in about 2000-, 3400-, 200- and 3400-fold losses, respectively, in binding affinity and 400-, 750-, 250- and 300-fold losses, respectively, in biological activity. Replacement of both Arg8 and Arg9 by lysine led to an analogue exhibiting the same pharmacological profile as the C-terminal hexapeptide of neurotensin. Interestingly, replacement of the Lys8-Lys9 peptide bond by the CH2NH bond produced an analogue exhibiting the same affinity for neurotensin receptors, but 10 times more potent in stimulating guinea pig ileum contraction. N-terminal protected analogues (by the Boc group) showed decreased potency as compared with their amino-free corresponding compounds.
Doulut
S
S
CCIPE, Faculté de Pharmacie, Montpellier, France.
Rodriguez
M
M
Lugrin
D
D
Vecchini
F
F
Kitabgi
P
P
Aumelas
A
A
Martinez
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000031:analogs & derivatives*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology
D009842:Oligopeptides; D010446:Peptide Fragments; D009496:Neurotensin