Ketomethylene and (cyanomethylene)amino pseudopeptide analogues of the C-terminal hexapeptide of neurotensin.
A series of pseudopeptide analogues of the C-terminal hexapeptide of neurotensin (NT8-13), namely [Tyr11 psi[COCH2]Phe12]-, [Ile12 psi[COCH2]Phe13]-, and [Tyr11 psi[CH(CN)NH]Ile12]NT8-13 with different stereochemistries, has been synthesized and evaluated for its potency in displacing labeled NT from rat cortex membranes. Ketomethylene pseudohexapeptides were prepared from the corresponding Boc-protected ketomethylene dipeptide derivatives, previously formed, using different solid phase synthesis (SPS) conditions, while (cyanomethylene)amino analogues were directly prepared by SPS using Fmoc strategy. H-Arg-Arg-Pro-Tyr psi[COCH2]-Phe-Leu-OH was nearly as potent as NT8-13 and [Phe12]NT8-13 in binding to the receptor. Comparison of the affinities for the pseudohexapeptides, here reported, with those of the psi-[CH2NH] analogues indicates the importance of the CO group in the amide or surrogate linkage at 11-12 and 12-13 positions in the receptor binding process.
González-Muñiz
R
R
Instituto de Química Médica (CSIC), Madrid, Spain.
García-López
M T
MT
Gómez-Monterrey
I
I
Herranz
R
R
Jimeno
M L
ML
Suárez-Gea
M L
ML
Johansen
N L
NL
Madsen
K
K
Thøgersen
H
H
Suzdak
P
P
D000097:Acetonitriles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D007659:Ketones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
D000097:Acetonitriles; D007659:Ketones; D009842:Oligopeptides; D010446:Peptide Fragments; D009496:Neurotensin; C054381:neurotensin (8-13)