Development of a bivalent dopamine D₂ receptor agonist

Julia Kühhorn, Angela Götz, Harald Hübner, Dawn Thompson, Peter Gmeiner

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Bivalent D₂ agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D₂ receptor antagonists of type 1, the bivalent agonist 2 was synthesized when a spacer built from 22 atoms was employed. Compared to the monovalent control compound 6 containing a capped spacer, the bis-aminoindane derivative 2 revealed substantial steepening of the competition curve, indicating a bivalent binding mode. Dimer-specific Hill slopes were not a result of varying functional properties because both the dopaminergic 2 and the monovalent control agent 6 proved to be D₂ agonists substantially inhibiting cAMP accumulation and inducing D₂ receptor internalization. Investigation of the heterobivalent ligands 8 and 9, containing an agonist and a phenylpiperazine-based antagonist pharmacophore, revealed moderate steepening of the displacement curves and antagonist to very weak partial agonist properties.

Original languageEnglish
Pages (from-to)7911-9
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number22
DOIs
Publication statusPublished - 24 Nov 2011

Keywords

  • Animals
  • Benzamides
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclic AMP
  • Drug Partial Agonism
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Piperazines
  • Protein Multimerization
  • Radioligand Assay
  • Receptors, Dopamine D2
  • Signal Transduction
  • Structure-Activity Relationship
  • Swine
  • Triazoles

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  • Cite this

    Kühhorn, J., Götz, A., Hübner, H., Thompson, D., & Gmeiner, P. (2011). Development of a bivalent dopamine D₂ receptor agonist. Journal of Medicinal Chemistry, 54(22), 7911-9. https://doi.org/10.1021/jm2009919