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

Mariana Spetea; Ilona P Berzetei-Gurske; Elena Guerrieri; Helmut Schmidhammer

doi:10.1021/jm301258w

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.

Authors

Mariana Spetea¹, Ilona P Berzetei-Gurske, Elena Guerrieri, Helmut Schmidhammer

Affiliation

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.

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*

Substances

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