Novel and Potent Dopamine D Receptor Go-Protein Biased Agonists.

The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D receptor (DR) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of DR agonists linking the DR unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved DR affinity and selectivity over sumanirole. Extensive functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full DR agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and β-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via DRs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.