Synthesis toward Bivalent Ligands for the Dopamine D<inf>2</inf> and Metabotropic Glutamate 5 Receptors

Mingcheng Qian, Elise Wouters, James A.R. Dalton, Martijn D.P. Risseeuw, René A.J. Crans, Christophe Stove, Jesús Giraldo, Kathleen Van Craenenbroeck, Serge Van Calenbergh

Research output: Contribution to journalArticleResearch

12 Citations (Scopus)

Abstract

© 2018 American Chemical Society. In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D2 receptor (D2R). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing D2R and mGluR5 compared to cells solely expressing D2R. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Additionally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing D2R and mGluR5. These results indicate that 22a is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that 22a had a 4-fold higher potency in stable D2R and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is able to simultaneously bind both receptors by passing between the TM5-TM6 interface and establishing six protein-ligand H-bonds.
Original languageEnglish
Pages (from-to)8212-8225
JournalJournal of Medicinal Chemistry
Volume61
DOIs
Publication statusPublished - 27 Sep 2018

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