Synthesis and stereoselective κ-receptor binding of methylated analogues of GR-89.696

Stereoselective synthesis of all four stereoisomers of methylated analogues 8 of the κ-receptor agonist GR-89.696 is presented. Starting with orthogonally protected piperazine derivatives (R,R)- 4 and (S,S)- 4, the reaction sequence involves oxidation, reductive amination and modification of the piperazine nitrogen protective groups. The configuration of the stereocentre in α-position to the pyrrolidine moiety is determined by X-ray structure analysis of (R,S)- 8. In receptor-binding studies with the radioligand U-69.593, the stereoisomer with (S)-configuration at both stereogenic centres (S,S)- 8 displayed the highest κ-receptor affinity with a K i-value of 0.67 nM.