Discovery and pharmacological evaluation of a diphenethylamine derivative (HS665), a highly potent and selective κ opioid receptor agonist

J Med Chem. 2012 Nov 26;55(22):10302-6. doi: 10.1021/jm301258w. Epub 2012 Nov 7.


Here we report on the design, synthesis, and biological characterization of novel κ opioid (KOP) receptor ligands of diphenethylamines. In opioid receptor binding and functional assays, the N-cyclobutylmethyl substituted derivative 4 (HS665) showed the highest affinity and selectivity for the KOP receptor and KOP agonist potency. Compound 4 inhibited acetic acid induced writhing after subcutaneous administration in mice via KOP receptor-mediated mechanisms, being equipotent as an analgesic to the KOP agonist U50,488.

Publication types

  • Evaluation Study

MeSH terms

  • Acetic Acid / toxicity
  • Analgesics / chemical synthesis
  • Analgesics / pharmacology*
  • Animals
  • Drug Discovery
  • Mice
  • Nociception / drug effects*
  • Pain / chemically induced
  • Pain / drug therapy*
  • Phenethylamines / chemical synthesis
  • Phenethylamines / pharmacology*
  • Receptors, Opioid, kappa / agonists*


  • 3-(2-((cyclobutylmethyl)(phenethyl)amino)ethyl)phenol
  • Analgesics
  • Phenethylamines
  • Receptors, Opioid, kappa
  • Acetic Acid