Homobivalent Dopamine D₂ Receptor Ligands Modulate the Dynamic Equilibrium of D₂ Monomers and Homo- and Heterodimers

Dopamine D₂ receptors (D₂Rs) are major targets in the treatment of psychiatric and neurodegenerative diseases. As with many other G protein-coupled receptors (GPCRs), D₂Rs interact within the cellular membrane, leading to a transient receptor homo- or heterodimerization. These interactions are known to alter ligand binding, signaling, and receptor trafficking. Bivalent ligands are ideally suited to target GPCR dimers and are composed of two pharmacophores connected by a spacer element. If properly designed, bivalent ligands are able to engange the two orthosteric binding sites of a GPCR dimer simultaneously. Taking advantage of previously developed ligands for heterodimers of D₂R and the neurotensin receptor 1 (NTSR1), we synthesized homobivalent ligands targeting D₂R. Employing bioluminescence resonance energy transfer, we found that the bivalent ligands 3b and 4b comprising a 92-atom spacer are able to foster D₂R-homodimerization while simultaneously reducing interactions of D₂R with NTSR1. Both receptors are coexpressed in the central nervous system and involved in important physiological processes. The newly developed bivalent ligands are excellent tools to further understand the pharmacological consequences of D₂R homo- and heterodimerization. Not limited to the dopaminergic system, modifying class A GPCRs' dynamic equilibrium between monomers, homomers, and heteromers with bivalent ligands may represent a novel pharmacological concept paving the way toward innovative drugs.