Dopamine D2 receptors dimers: how can we pharmacologically target them?

Dopamine D2 and D3 receptors are important pharmacological targets in Schizophrenia and Parkinson’s disease. Intriguingly, many studies have shown that they form homo- and heterodimers, and they can be targeted in specific tissues with new drugs. In this direction, many efforts have been made to develop new molecules that are able to interact with these receptor dimeric complexes. Among various strategies for targeting dopamine receptors dimers, two distinct classes of compounds, such as bivalent and bitopic ligands, have gained particular attention and their use in pharmacology looks promising. Bivalent ligands target the orthosteric sites of the two monomers in the dimeric complex. Some studies have however questioned the bivalent properties of these ligands, which might interact with a receptor dimer or simply with a monomer and additionally, their high molecular weight makes them unfavorable for clinical use. The bitopic ligands target both the orthosteric and the allosteric sites in one monomeric receptor, thereby increasing selectivity over receptor subtypes. For dopamine D2 and D3 receptors, the bitopic ligand SB269,652 has been specifically demonstrated for dual action (dualsteric). This compound switches its antagonistic properties in favor of negative allosterism in the presence of dopamine receptor dimers and may offer therapeutic advantages and better tolerability in comparison with pure antagonists at D2 receptors. Recent studies have further complicated this picture by pointing out that dimer formation is a dynamic process where dimers dissociate and re-associate quickly, and this equilibrium is influenced by the pharmacological characteristics of the ligand where some compounds are able to increase dimer formation.