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.
Mariana Spetea  1 ,  Ilona P Berzetei-Gurske ,  Elena Guerrieri ,  Helmut Schmidhammer
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
PMID: 23134120 DOI: 10.1021/jm301258w
Abstract

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.