Synthesis and human neurotensin receptor binding activities of neurotensin(8-13) analogues containing position 8 alpha-azido-N-alkylated derivatives of ornithine, lysine, and homolysine

J Med Chem. 1999 Nov 18;42(23):4914-8. doi: 10.1021/jm9903444.

Abstract

A series of neurotensin(8-13) (NT) analogues were synthesized through intermediates in which the N-terminal Arg(8) was replaced by various omega-bromo-2(S)-azido residues spanning 3-5 methylene units in side-chain length. Subsequent nucleophilic substitution of the omega-bromo groups with ammonia, methylamine, dimethylamine, or trimethylamine provided peptides containing N-terminal 2(S)-azido residues containing primary through quaternary N-alkylated side chains corresponding in length to ornithine, Lys, and homolysine. The synthetic procedure appears applicable for incorporation of a wide variety of amine-containing nonnatural amino acids into peptides. The particular modifications were intended to enhance physiochemical properties of NT(8-13) responsible for human NT 1 receptor (hNTR) binding, overall lipophilicity, and stability that may influence the potency of the peptides in vivo. When the peptides were tested for hNTR binding, the affinities in each series followed the order primary > secondary > tertiary > quaternary amine with the homolysine side-chain length being favored. All analogues possess binding affinities between acetyl-NT(8-13) and NT(8-13) indicating that the sterically less bulky alpha-azido may be inherently preferable to the acetyl group for N-terminal protection. This study extends the strategy of modifying amine-containing drugs through alkylations to peptide modification. The set of alkylated side chains also offers a new method of steric selection between receptor subtypes and could be used to modify the properties and biological effects of any peptide that contains cationic residues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azides / chemical synthesis*
  • Azides / chemistry
  • Azides / metabolism
  • CHO Cells
  • Cricetinae
  • Humans
  • Lysine / analogs & derivatives
  • Lysine / chemical synthesis*
  • Lysine / chemistry
  • Lysine / metabolism
  • Neurotensin / chemical synthesis*
  • Neurotensin / chemistry
  • Neurotensin / metabolism
  • Ornithine / analogs & derivatives
  • Ornithine / chemical synthesis*
  • Ornithine / chemistry
  • Ornithine / metabolism
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Radioligand Assay
  • Receptors, Neurotensin / metabolism*
  • Structure-Activity Relationship

Substances

  • Azides
  • Peptide Fragments
  • Receptors, Neurotensin
  • Neurotensin
  • neurotensin (8-13)
  • Ornithine
  • Lysine