title: Synthesis and stereoselective kappa-receptor binding of methylated analogues of GR-89.696.
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.
authors: Institut für Anorganische und Analytische Chemie der Universität Freiburg, 21, 79104 Freiburg, Albertstrasse, Germany.
authors: C
authors: C
authors: Röhr
authors: S
authors: S
authors: Soukara
authors: B
authors: B
authors: Wünsch
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D008566:Membranes / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism*; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism*; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000316:Adrenergic alpha-Agonists; D018712:Analgesics, Non-Narcotic; D010879:Piperazines; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C071609:GR 89696