Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 17, Pages 7579-7590Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00981
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Funding
- Austrian Science Fund [FWF: TRP19-B18]
- University of Innsbruck
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We previously reported on a series of small molecules targeting the kappa-opioid (KOP) receptor featuring a diphenethylamine scaffold and showed the promise of these ligands as effective analgesics with reduced liability for adverse effects. This study expands the structure-a ctivity relationships on our original series by presenting several modifications in the lead compounds 1 (HS665) and 2 (HS666). A library of new diphenethylamines was designed, synthesized, and pharmacologically evaluated. In comparison with 1 and 2, the KOP receptor affinity, selectivity, and agonist activity were modulated by introducing bulkier N-substituents, a 2-fluoro substitution, and additional hydroxyl groups at positions 3' and 4'. Several analogues showed subnanomolar affinity and excellent KOP receptor selectivity acting as full or partial agonists, and one as an antagonist. The new diphenethylamines displayed antinociceptive efficacies with increased potencies than U50,488, 1 and 2 in the writhing assay and without inducing motor dysfunction after sc administration in mice.
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