Functional selectivity of ligands at the dopamine D2L dopamine receptor
A D2R cellular model is developed using a single cell line background to assess the activation of different signaling pathways downstream of the D1R and new examples of previously unappreciated functionally selective ligands are discovered.
Abstract
The dopamine D2 receptor (D2R) is an important drug target that exerts its functions through several signaling pathways. It has been previously shown that different ligands can activate these signaling pathways with distinct potencies and efficacies (i.e. functional selective ligands). Additionally, recent studies suggest that selective activation of individual D2R signaling pathways may provide safer and more effective drug therapies. The objective of the present study was to develop a D2R cellular model using a single cell line background to assess the activation of different signaling pathways downstream of the D2R. By using a single cell background to assess activation of distinct signaling pathways, we eliminate potential confounds associated with variability in the expression levels of the D2R or other signal transduction proteins involved in receptor signaling. We used CHO‐D2L cells from DiscoveRx in the PathHunter system to detect β‐arrestin‐2 recruitment by the D2R. Additional protocols were developed to assess Gαi/o, Gβγ, and MAPK signaling. The ligands tested include many previously characterized D2 receptor modulators that are currently used for treatment of Parkinson's disease and schizophrenia (e.g. pramipexole and aripiprazole). Using this approach we have discovered new examples of previously unappreciated functionally selective ligands (supported by MH60397 and BBRF).