Pharmacological targeting of G protein-coupled receptor heteromers

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D₁ and D₃ receptors (D₁R and D₃R) influences the pharmacological properties of three structurally similar selective dopamine D₃R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D₁R-D₃R heteromer-disrupting peptides, it could be demonstrated that the three D₃R ligands display different D₁R-D₃R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D₁R-mediated signaling in the D₁R-D₃R heteromer; PG01037, acting as a D₃R antagonist cross-antagonized D₁R-mediated signaling in the D₁R-D₃R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D₁R-D₃R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D₃R ligands that are dependent on D₁R-D₃R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D₃R ligands in vivo. The results supported the involvement of D₁R-D₃R heteromers in the locomotor activation by D₁R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D₁R-D₃R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.