Enantiomerically Pure Quinoline‐Based κ‐Opioid Receptor Agonists: Chemoenzymatic Synthesis and Pharmacological Evaluation

Racemic (K)‐opioid receptor (KOR) agonist 2‐(3,4‐dichlorophenyl)‐1‐[(4aRS,8SR,8aSR)‐8‐(pyrrolidin‐1‐yl)‐3,4,4a,5,6,7,8,8a‐octahydroquinolin‐1(2H)‐yl]ethan‐1‐one ((±)‐4) was prepared in a diastereoselective synthesis. The first key step of the synthesis was the diastereoselective hydrogenation of the silyl ether of 1,2,3,4‐tetrahydroquinoin‐8‐ol ((±)‐9) to afford cis,cis‐configured perhydroquinoline derivative (±)‐10. Removal of the TBDMS protecting group led to a β‐aminoalcohol that reacted with SO(2)Cl(2) to form an oxathiazolidine. Nucleophilic substitution with pyrrolidine resulted in the desired cis,trans‐configured perhydroquinoline upon inversion of the configuration. In order to obtain enantiomerically pure KOR agonists 4 (99.8 % ee) and ent‐4 (99.0 % ee), 1,2,3,4‐tetrahydroquinolin‐8‐ols (R)‐8 (99.1 % ee) and (S)‐8 (98.4 % ee) were resolved by an enantioselective acetylation catalyzed by Amano lipase PS‐IM. The absolute configuration was determined by CD spectroscopy. The 4aR,8S,8aS‐configured enantiomer 4 showed sub‐nanomolar KOR affinity (K (i)=0.81 nM), which is more than 200 times higher than the KOR affinity of its enantiomer ent‐4. In the cAMP assay and the Tango β‐arrestin‐2 recruitment assay, 4 behaved as a KOR agonist. Upon incubation of human macrophages, human dendritic cells, and mouse myeloid immune cells with 4, the number of cells expressing co‐stimulatory receptor CD86 and proinflammatory cytokines interleukin 6 and tumor necrosis factor α was significantly reduced; this indicates the strong anti‐inflammatory activity of 4. The anti‐inflammatory effects correlated well with the KOR affinity: (4aR,8S,8aS)‐4 was slightly more potent than the racemic mixture (±)‐4, and the distomer ent‐4 was almost inactive.