Discovery of a true bivalent dopamine D2 receptor agonist

Mingcheng Qian, Adrián Ricarte, Elise Wouters, James A.R. Dalton, Martijn D.P. Risseeuw, Jesús Giraldo, Serge Van Calenbergh*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D2R. Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a D2R homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays.

Original languageEnglish
Article number113151
JournalEuropean Journal of Medicinal Chemistry
Volume212
Issue number15
DOIs
Publication statusPublished - 15 Feb 2021

Keywords

  • Binding affinity
  • Bivalent ligands
  • cAMP
  • DR homodimer
  • Molecular modeling

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