Background: Dopamine D2 and D3 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 D2 and D3 receptors
were analyzed by using single particle tracking microscopy.
Results: The specific targeting of dopamine D2 and D3 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 D2 and D3 receptors, a new dualsteric molecule SB269,652
was shown to have selective negative allosteric properties across D2 and D3 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 D2 and D3 receptors and pave the way for a new generation
of antipsychotic drugs.