Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists

TL;DR

This paper describes the synthesis and testing of a new compound that selectively activates the κ receptor with high specificity.

Contribution

A novel perhydroquinoxaline-based κ receptor agonist with high selectivity and structural confirmation via X-ray analysis is presented.

Findings

Compound 14 showed moderate κ receptor affinity (Ki = 599 nM).

It exhibited high selectivity over μ, δ, σ1, and σ2 receptors.

X-ray crystal structure analysis confirmed the compound's relative configuration.

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 X-ray 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.

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