Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer

J Med Chem. 2011 Dec 8;54(23):8000-12. doi: 10.1021/jm200789r. Epub 2011 Oct 26.


Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for κ opioid receptor binding while having a K(i) = 35.8 nM for μ opioid receptors and a K(i) = 211 nM for δ opioid receptor binding. Compound 25 was also a potent antagonist of κ opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-γ-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Brain / metabolism
  • CHO Cells
  • Chromatography, Liquid
  • Cricetinae
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tandem Mass Spectrometry


  • 3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide
  • 3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide
  • Benzamides
  • Pyrrolidines
  • Receptors, Opioid, kappa