Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y4 Receptor Agonist Derived by an Olefin Metathesis Approach

J Med Chem. 2016 Jul 14;59(13):6059-69. doi: 10.1021/acs.jmedchem.6b00310. Epub 2016 Jun 28.

Abstract

The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors and as a lead compound for antiobesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labeled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)-diaminosuberoyl containing peptide, (R,R)-1, had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore, the sulfo-Cy5 labeled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors.

MeSH terms

  • Alkenes / chemistry*
  • Alkenes / pharmacology*
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacology*
  • Carbocyanines / chemistry
  • HEK293 Cells
  • Humans
  • Optical Imaging
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Receptors, Neuropeptide Y / agonists*
  • Receptors, Neuropeptide Y / analysis
  • Receptors, Neuropeptide Y / metabolism

Substances

  • Alkenes
  • Anti-Obesity Agents
  • Carbocyanines
  • Peptides
  • Receptors, Neuropeptide Y
  • cyanine dye 5
  • neuropeptide Y4 receptor