The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D 2 receptor (D 2 R) 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 D 2 R agonists linking the D 2 R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D 2 R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D 2 R 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 D 2 Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.

Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.

The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D G-protein biased agonism with an EC in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in DR-BRET functional assays.