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Study of G protein-coupled receptors dimerization : from bivalent ligands to drug-like small molecules Ghent University

Mingcheng Qian, Zhengyang Sun, Xin Chen, Serge Van Calenbergh
In the past decades an increasing number of studies revealed that G protein-coupled receptors (GPCRs) are capable of forming dimers or even higher-ordered oligomers, which may modulate receptor function and act as potential drug targets. In this review, we briefly summarized the design strategy of bivalent GPCR ligands and mainly focused on how to use them to study and/or detect GPCP dimerization in vitro and in vivo. Bivalent ligands show ...

Discovery of a true bivalent dopamine D2 receptor agonist Ghent University

Mingcheng Qian, Adrián Ricarte, Elise Wouters, James A.R. Dalton, Martijn Risseeuw, Jesús Giraldo, Serge Van Calenbergh
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 D-2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D-2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D2R. Molecular modeling revealed that 11c can ...

Design, synthesis and characterization of a new series of fluorescent metabotropic glutamate receptor type 5 negative allosteric modulators Ghent University

Víctor Fernández-Dueñas, Mingcheng Qian, Josep Argerich, Carolina Amaral, Martijn Risseeuw, Serge Van Calenbergh, Francisco Ciruela
In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system ...

Synthesis toward bivalent ligands for the dopamine D2 and metabotropic glutamate 5 receptors Ghent University

Mingcheng Qian, Elise Wouters, James AR Dalton, Martijn Risseeuw, René Crans, Christophe Stove, Jesús Giraldo, Kathleen Van Craenenbroeck, Serge Van Calenbergh
In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D-2 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. ...