Development of a bivalent dopamine D 2 receptor agonist

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

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Bivalent D 2 agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D 2 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 D 2 agonists substantially inhibiting cAMP accumulation and inducing D 2 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 (US)
Pages (from-to)7911-7919
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number22
DOIs
StatePublished - Nov 24 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Kühhorn, J., Götz, A., Hübner, H., Thompson, D., Whistler, J., & Gmeiner, P. (2011). Development of a bivalent dopamine D 2 receptor agonist. Journal of Medicinal Chemistry, 54(22), 7911-7919. https://doi.org/10.1021/jm2009919