Dopamine D2 Receptors Dimers: How can we Pharmacologically Target Them?

Abstract

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.

Keywords: G protein-coupled receptor (GPCR); and antipsychotics; bivalent ligand; dimerization; dopamine receptors; dualsteric ligand; single-molecule microscopy.

Fig. (1)

A schematic view of bivalent-ligand binding modalities for GPCR dimers. (A) A homobivalent ligand consisting of two identical pharmacophores attached to respective linkers and connected by a spacer of variable length targeting simultaneously the orthosteric sites of a homodimer complex. (B) A heterobivalent ligand consisting of two different pharmacophores targeting simultaneously the orthosteric sites of a heterodimer complex. (C) A heterobivalent ligand consisting of two different pharmacophores targeting simultaneously an orthosteric site of one monomer and an allosteric site of other monomer of a heterodimer complex. (D) Dual acting homobivalent ligands consisting of two identical pharmacophores targeting the orthosteric sites of a homodimer complex with two different molecules and the simultaneous binding is not required. (E) Dual acting heterobivalent ligands consisting of two different pharmacophores targeting the orthosteric sites of a heterodimer complex with two different molecules and the simultaneous binding is not required. (F) A bitopic compound consisting of two different pharmacophores connected by a linker of variable length targeting both the orthosteric and the allosteric sites of the same monomer of a homodimeric complex. The binding of the dualsteric ligand induces a negative allosterism on the other monomer.

Fig. (2)

Dualsteric binding mechanism of SB269,652 at dopamine D₂ receptor. [A] Binding of dopamine at the orthosteric site of D₂ monomer. [B] Binding of dualsteric compound SB269,652 at the orthosteric and allosteric sites of D₂ monomer. This prevents binding of dopamine at the orthosteric site through a competitive mechanism. [C] Binding of dualsteric compound SB269,652 at the orthosteric and allosteric sites of the D₂ monomer of a homodimeric complex. This binding induces a conformational change at the othosteric site on the other monomer (negative allosterism), thereby reducing the dopamine affinity.

Fig. (3)

Pharmacological modulation by different ligands of the monomer-dimer equilibrium percentage in D₂ receptor. [A] In absence of ligand (basal condition), the monomer-dimer equilibrium ratio is around 70% monomers to 30% dimers. [B] Under the presence of an antagonist, the monomer-dimer equilibrium ratio is around 70% monomers to 30% dimers. [C] Under the presence of an agonist, the monomer-dimer equilibrium ratio is around 55% monomers to 45% dimers. [D] Under the influence of a bifunctional antagonist, the monomer-dimer equilibrium ratio is around 35% monomers to 65% dimers.