NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids

Bioorg Med Chem. 2017 Jan 1;25(1):350-359. doi: 10.1016/j.bmc.2016.10.039. Epub 2016 Nov 1.

Abstract

Stimulation of the NTS2 neurotensin receptor causes antipsychotic effects and leads to a promotion of the μ-opioid-independent antinociception, which is important in the modulation of tonic pain sensitivity. We report the synthesis and properties of a small library of peptidic agonists based on the active neurotensin fragment NT(8-13). Two tetrahydrofuran amino acid derivatives were synthesized to replace Tyr11 in NT(8-13). Additionally, Arg8, Arg9, and Ile12 of the lead peptide were exchanged by Lys, Lys, and Gly, respectively. The new compounds showed substantial NTS2 binding affinity and up to 1000-fold selectivity over NTS1. The highest selectivity (Ki(NTS2): 29nM, Ki(NTS1): 35,000nM) was observed for the peptide analog 17Rtrans.

Keywords: Neurotensin; Non-natural amino acid; Peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetulus
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Molecular Mimicry
  • Neurotensin / chemical synthesis
  • Neurotensin / chemistry
  • Neurotensin / pharmacology*
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Pyrrolidonecarboxylic Acid / analogs & derivatives*
  • Pyrrolidonecarboxylic Acid / chemical synthesis
  • Pyrrolidonecarboxylic Acid / chemistry
  • Pyrrolidonecarboxylic Acid / pharmacology
  • Receptors, Neurotensin / agonists*

Substances

  • Furans
  • NTSR2 protein, human
  • Peptide Fragments
  • Peptidomimetics
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • Neurotensin
  • neurotensin (1-8)
  • Pyrrolidonecarboxylic Acid