European Journal of Medicinal Chemistry 2001-02-01

Synthesis and stereoselective kappa-receptor binding of methylated analogues of GR-89.696.

C Röhr, S Soukara, B Wünsch

Index: Eur. J. Med. Chem. 36(2) , 211-4, (2001)

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Abstract

Stereoselective synthesis of all four stereoisomers of methylated analogues 8 of the kappa-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 alpha-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 kappa-receptor affinity with a K(i)-value of 0.67 nM.