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 D(1) and D(3) receptors (D(1)R and D(3)R) influences the pharmacological properties of three structurally similar selective dopamine D(3)R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D(1)R-D(3)R heteromer-disrupting peptides, it could be demonstrated that the three D(3)R ligands display different D(1)R-D(3)R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D(1)R-mediated signaling in the D(1)R-D(3)R heteromer; PG01037, acting as a D(3)R antagonist cross-antagonized D(1)R-mediated signaling in the D(1)R-D(3)R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D(1)R-D(3)R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D(3)R ligands that are dependent on D(1)R-D(3)R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D(3)R ligands in vivo. The results supported the involvement of D(1)R-D(3)R heteromers in the locomotor activation by D(1)R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D(1)R-D(3)R 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.