Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs.

Introduction : G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins highly expressed in the brain that are involved in almost all functions of the CNS. During the last twenty years, a large number of GPCRs have been reported to form homodimers, heterodimers and higher order oligomers. Areas covered : This review summarizes the functional and pharmacological characteristics of the dopamine D ₁ receptor (D ₁ R) interactome constituted by heteromers with GPCRs or non-GPCRs. The review also focuses on heteromer-selective ligands reported for GPCRs, including those for the receptor-based interactome of D ₁ R. Expert opinion : Since the D ₁ R plays a key role in basal ganglia motor control, where all the mentioned D ₁ R heteromers are present, the study of allosteric interactions within the D ₁ R interactome may be of high therapeutic interest for treating motor dysfunction. Moreover, several of these heteromers have also been detected in the prefrontal cortex and hippocampus, where they are involved in learning, memory and attention dysfunction. We propose that drugs targeting specific D ₁ R heteromers in the CNS will be more effective and safer, resulting in a reduction of side effects compared with traditional drugs targeting monomeric receptors. Heteromer-selective ligands will have a big impact on drug development with many pharmacological and clinical implications.