Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor

The dopamine D2/D3 receptor (D(2)R/D(3)R) agonists are used as therapeutics for Parkinson’s disease (PD) and other motor disorders. Selective targeting of D(3)R over D(2)R is attractive because of D(3)R’s restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D(2)R and D(3)R poses a challenge in the development of D(3)R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D(3)R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D(3)R and D(2)R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D(3)R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D(3)R over D(2)R selectivity, and G protein bias at D(3)R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D(3)R and support further evaluation of functionally biased D(3)R agonists for their therapeutic potential.