Ketomethylene and (cyanomethylene)amino pseudopeptide analogues of the C-terminal hexapeptide of neurotensin

J Med Chem. 1995 Mar 17;38(6):1015-21. doi: 10.1021/jm00006a021.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetonitriles / chemical synthesis*
  • Acetonitriles / metabolism
  • Acetonitriles / pharmacology*
  • Amino Acid Sequence
  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Ketones / chemical synthesis
  • Ketones / metabolism
  • Ketones / pharmacology
  • Molecular Sequence Data
  • Neurotensin / analogs & derivatives*
  • Neurotensin / chemical synthesis
  • Neurotensin / metabolism
  • Neurotensin / pharmacology
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Rats

Substances

  • Acetonitriles
  • Ketones
  • Oligopeptides
  • Peptide Fragments
  • Neurotensin
  • neurotensin (8-13)