Discovery and Pharmacological Evaluation of a Diphenethylamine Derivative (HS665), a Highly Potent and Selective κ Opioid Receptor Agonist

Here we report on the design, synthesis, and biological characterization of novel kappa 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.