Dopamine D(2) Receptors Dimers: How can we Pharmacologically Target Them?

BACKGROUND: Dopamine D(2) and D(3) receptors can form homo- and heterodimers and are important targets in Schizophrenia and Parkinson’s. Recently, many efforts have been made to pharmacologically target these receptor complexes. This review focuses on various strategies to act specifically on dopamine receptor dimers, that are transiently formed. METHODS: Various binding and functional assays were reviewed to study the properties of bivalent ligands, particularly for the dualsteric compound SB269,652. The dimerization of D(2) and D(3) receptors were analyzed by using single particle tracking microscopy. RESULTS: The specific targeting of dopamine D(2) and D(3) dimers can be achieved with bifunctional ligands, composed of two pharmacophores binding the two orthosteric sites of the dimeric complex. If the target is a homodimer, then the ligand is homobivalent. Instead, if the target is a heterodimer, then the ligand is heterobivalent. However, there is some concern regarding pharmacokinetics and binding properties of such drugs. Recently, a new generation of bitopic compounds with dualsteric properties have been discovered that bind to the orthosteric and the allosteric sites in one monomeric receptor. Regarding dopamine D(2) and D(3) receptors, a new dualsteric molecule SB269,652 was shown to have selective negative allosteric properties across D(2) and D(3) homodimers, but it behaves as an orthosteric antagonist on receptor monomer. Targeting dimers is also complicated as they are transiently formed with varying monomer/dimer ratio. Furthermore, this ratio can be altered by administering an agonist or a bifunctional antagonist. CONCLUSION: Last 15 years have witnessed an explosive amount of work aimed at generating bifunctional compounds as a novel strategy to target GPCR homo- and heterodimers, including dopamine receptors. Their clinical use is far from trivial, but, at least, they have been used to validate the existence of receptor dimers in-vitro and in-vivo. The dualsteric compound SB269, 652, with its peculiar pharmacological profile, may offer therapeutic advantages and a better tolerability in comparison with pure antagonists at D(2) and D(3) receptors and pave the way for a new generation of antipsychotic drugs.