Stereoselective synthesis and biological evaluation of perhydroquinoxaline-based kappa receptor agonists.

J. Hoffmann, D. Schepmann, C. Daniliuc, M. Bermúdez, B. Wünsch

Abstract

The hydroxylated perhydroquinoxaline 14 was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of 14 comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (4). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane 7 by the reaction of dialdehyde 6 with benzylamine and nitromethane. The piperazine ring was annulated by the reaction of silyloxy-substituted cyclohexanetriamine 8 with dimethyl oxalate. The pharmacophoric structural elements characteristic for κ receptor agonists were finally introduced by functional group modifications. The structure including the relative configuration of the tetrasubstituted cyclohexane derivative (2r,5s)-7a and the perhydroquinoxaline 9 was determined unequivocally by Xray crystal structure analysis. The hydroxylated perhydroquinoxaline 14 showed moderate κ receptor affinity (Ki = 599 nM) and high selectivity over μ, δ, σ1, and σ2 receptors. An ionic interaction between the protonated pyrrolidine of 14 and D138 of κ receptor anchors 14 in the κ receptor binding pocket.