Identification of a novel dopaminergic agonist that selectively activates the D2 dopamine receptor

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In order to identify novel ligands with selectivity for the D2 dopamine (DA) receptor (DAR), we have interrogated small molecule chemical libraries using live cell functional assays and high throughput screening (HTS) techniques. Our primary HTS assay involves D2 DAR activation of a chimeric G protein, Gqi5, which links D2 DAR activation to Ca2+ mobilization. This process led to the identification of a ligand (compound A) that selectively activates the D2 DAR in comparison with other DAR subtypes. We found that compound A exhibits full agonist activity with EC50 values ranging from 100 nM – 1 μM using three different functional assays for the D2 DAR; Ca2+ mobilization, inhibition of cAMP accumulation, and β‐arrestin recruitment. Using β‐arrestin recruitment assays to compare with other DARs, we found that compound A has no activity at D1‐like DARs (D1 and D5), weak antagonist activity at D4 DARs (at concentrations > 10 μM), and either weak partial agonist (<20% of the DA response) or full antagonist activity at D3 DARs. Radioligand binding assays revealed that compound A exhibits Ki values of ~1 μM and ~100 nM for the D2 and D3 DARs, respectively. In summary, compound A is a full and selective agonist at the D2 DAR, although it is also functions as a D3 DAR antagonist. This is the first known compound that functionally discriminates between the D2 and D3 DARs and selectively activates the D2 DAR in the absence of D3 DAR activation.