Diastereoselective synthesis of 1,4,8-trisubstituted perhydroquinolines as novel κ receptor agonists.

Flämig L; Felix Zhu W; Hoffmann K; Daniliuc C; Schepmann D; Glorius F; Bermúdez M; Loser K; Wünsch B

Abstract

Agonists of the κ-opioid receptor are useful drugs for the treatment of severe pain, itching skin diseases and inflammatory and immunological diseases. Herein, novel κ agonists with the κ-pharmacophoric ethylenediamine system embedded in a rigid decahydroquinoline scaffold (6) were designed, synthesized and pharmacologically evaluated. The synthesis of decahydroquinolines 6 consisted of three parts: (1) synthesis of 4,8-disubstituted tetrahydroquinolines 14; (2) diastereoselective hydrogenation of tetrahydroquinolines 14 to afford decahydroquinolines 17; and (3) stereoselective introduction of the pyrrolidine ring at the 8-position and various acyl moieties at the 1-position. The dichlorophenylacetyl and fluorophenylacetyl derivatives 6a (Ki = 86 nM) and 6b (Ki = 134 nM) showed considerably lower κ affinity than the lead compounds 4 (Ki = 0.81 nM) and 5 (Ki = 0.25 nM). In docking studies, the NH moiety of the exocyclic carbamates 6a and 6b served as an H-bond donor towards the OH moiety of Y239, whereas the methoxycarbonyl moiety of endocyclic carbamate 5 formed a beneficial H-bond with the NH backbone of L212. The lower κ affinity of 6a and 6b was at least partially compensated by increased polarity, leading to promising LLE values of 5.69 and 6.87, respectively. Both κ agonists 6a and 6b revealed high selectivity over µ- and δ-opioid receptors and high metabolic stability in the presence of mouse liver microsomes and NADPH. The anti-inflammatory activity of the κ receptor agonist 6a was investigated with human peripheral blood mononuclear cells stimulated with lipopolysaccharide, and the effects were compared with those of the lead compounds 4 and 5. Methyl carbamate 6a exhibited the smallest reduction in pro-inflammatory monocyte subsets and did not affect cytokine secretion. It was concluded that 6a had a substantially weaker anti-inflammatory activity than the lead compounds 4 and 5.