Design, synthesis and biological evaluation of N-hydroxy- aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists

Aminobenzyloxyarylamide derivatives la-i and 2a-t were designed and synthesized as novel selective kappa opioid receptor (KOR) antagonists. The benzoyl amide moiety of LY2456302 was changed into N-hydroxybenzamide and benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity or selectivity for KOR. All target compounds were evaluated in radioligand binding assays for opioid receptor binding affinity. These efforts led to the identification of compound lc (kappa K-i = 179.9 nM), which exhibited high affinity for KOR. Moreover, the selectivity of KOR over MOR and DOR increased nearly 2-fold and 7-fold, respectively, compared with ( +/- )LY2456302.