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

Eur J Med Chem. 2001 Feb;36(2):211-4. doi: 10.1016/s0223-5234(00)01208-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / chemical synthesis*
  • Adrenergic alpha-Agonists / metabolism*
  • Analgesics, Non-Narcotic / chemical synthesis*
  • Analgesics, Non-Narcotic / metabolism*
  • Animals
  • Brain / cytology
  • Crystallography, X-Ray
  • Guinea Pigs
  • Membranes / chemistry
  • Piperazines / chemical synthesis*
  • Piperazines / metabolism*
  • Protein Binding
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / metabolism*
  • Radioligand Assay
  • Receptors, Opioid, kappa / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adrenergic alpha-Agonists
  • Analgesics, Non-Narcotic
  • Piperazines
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • GR 89696