Discovery of a true bivalent dopamine D2 receptor agonist

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. [Display omitted] •Synthesis of possible bivalent ligands for dopamine D2 receptor homodimers.•IndBipAlk-based bivalent ligands show a cooperative binding, which increases with elongation of the linker.•Bivalent ligand 11c displays a 16 times lower Ki value than its parent monomeric alkyne 2.•Docking indicates that 11c simultaneously binds both protomers in a relaxed conformation through the interface of TM5-TM6.