Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity<i>in Vivo</i>

Abstract

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [³⁵S]GTPγS assay, and high selectivity over μ, δ, σ₁, and σ₂ receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (K_i = 0.63 nM) and highly selective κ agonist (EC₅₀ = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.