Guanidine-acylguanidine bioisosteric approach in the design of radioligands: synthesis of a tritium-labeled N(G)-propionylargininamide ([3H]-UR-MK114) as a highly potent and selective neuropeptide Y Y1 receptor antagonist

J Med Chem. 2008 Dec 25;51(24):8168-72. doi: 10.1021/jm801018u.

Abstract

Synthesis and characterization of (R)-N(alpha)-(2,2-diphenylacetyl)-N-(4-hydroxybenzyl)-N(omega)-([2,3-(3)H]-propanoyl)argininamide ([(3)H]-UR-MK114), an easily accessible tritium-labeled NPY Y(1) receptor (Y(1)R) antagonist (K(B): 0.8 nM, calcium assay, HEL cells) derived from the (R)-argininamide BIBP 3226, is reported. The radioligand binds with high affinity (K(D), saturation: 1.2 nM, kinetic experiments: 1.1 nM, SK-N-MC cells) and selectivity for Y(1)R over Y(2), Y(4), and Y(5) receptors. The title compound is a useful pharmacological tool for the determination of Y(1)R ligand affinities, quantification of Y(1)R binding sites, and autoradiography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / analogs & derivatives*
  • Arginine / chemical synthesis
  • Arginine / chemistry
  • Arginine / pharmacology
  • Binding Sites
  • CHO Cells
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods*
  • Chromatography, High Pressure Liquid
  • Cricetinae
  • Cricetulus
  • Drug Design
  • Guanidine / chemistry*
  • Humans
  • Kinetics
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Receptors, Neuropeptide Y / chemistry
  • Tritium / chemistry*

Substances

  • Nalpha-(2,2-diphenylacetyl)-N-(4-hydroxybenzyl)-Nomega-propanoylargininamide
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • Tritium
  • argininamide
  • Arginine
  • Guanidine