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Discovery of a true bivalent dopamine D2 receptor agonist
Mingcheng Qian1, Adrián Ricarte2, Elise Wouters3
1Department of Medicinal Chemistry, School of Pharmacy, Changzhou University, Changzhou, 213164, Jiangsu, China; Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
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.
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