New 2-thioether-substituted Apomorphines as Potent and Selective Dopamine D₂ Receptor Agonists

Eur J Med Chem. 2011 Jul;46(7):2992-9. doi: 10.1016/j.ejmech.2011.04.028. Epub 2011 Apr 22.

Abstract

A set of novel apomorphine derivatives were synthesized with diversely functionalized side chains in the proximity of position 2 of the aporphine skeleton. Amino and/or carboxylic functions were introduced to this region of the backbone to test their pharmacological effects. During the synthesis of 2-(S-3-mercaptopropionic acid)-derivative a heteroring-fused congener was also isolated. The structural elucidation confirmed that the formation of this product was in accordance with our previous observations on the reaction of thebaine (2) with thiosalycilic acid. All the novel apomorphine congeners 4a-g were neuropharmacologically characterized to discover their dopaminergic profiles. Two derivatives were identified as D(2) full agonists equipotent with apomorphine (1) having significantly increased D(2)/D(1) selectivity ratios.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Mercaptopropionic Acid / chemistry
  • Animals
  • Apomorphine / analogs & derivatives
  • Apomorphine / chemical synthesis*
  • Apomorphine / pharmacology
  • CHO Cells
  • Cell Line
  • Cell Membrane / chemistry*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetulus
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / pharmacology
  • Fibroblasts / chemistry
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Molecular Docking Simulation
  • Rats
  • Receptors, Dopamine D1 / agonists*
  • Receptors, Dopamine D1 / chemistry
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / metabolism
  • Salicylates / chemistry
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemistry
  • Thebaine / chemistry

Substances

  • Dopamine Agonists
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Salicylates
  • Sulfhydryl Compounds
  • Thebaine
  • 3-Mercaptopropionic Acid
  • thiosalicylic acid
  • Apomorphine