Chirality of novel bitopic agonists determine unique pharmacology at the dopamine 2 and 3 receptors

Abstract

The dopamine 2 and 3 receptors (D2R and D3R) are well‐characterized targets for neuropsychiatric disorders. D2R/D3R agonists are used as add‐on therapies for Parkinson’s disease (PD) and have been studied for other motor‐associated disorders. Selectively targeting D3R over D2R is attractive for two reasons: i) restricted tissue distribution of D3R compared to D2R exhibits potential for lesser side‐effects; ii) there is evidence for dominant role of D3R over D2R for neuroprotective and neurorestorative actions of dopaminergic agonists used for the treatment of PD. However, lack of highly selective D3R agonists has made it difficult to separate the D3R vs. D2R physiological effects. Indeed, the development of highly selective D3R agonists has remained a challenge due to their 78% sequence identity in the transmembrane domain. To improve the outlook of D3R agonist‐based medication development, based on a potent D3R‐selective agonist PF592,379, we have designed, synthesized, and pharmacologically characterized bitopic ligands with a secondary pharmacophore tethered to the PF592,379 primary pharmacophore by a linker. Using BRET based functional assays that measure G‐protein activation and β‐arrestin recruitment, we characterized these bitopic ligands at both D3R and D2R. We found that the addition of secondary pharmacophore to the PF592,379 scaffold improved potency at D3R in G‐protein activation with maximal efficacy similar or higher than that of the parent compound. In contrast, the potencies at D3R in recruitment of β‐arrestin remained the same. Some of these compounds also showed modest D3R over D2R selectivity. Interestingly, certain combinations of secondary pharmacophores and linkers resulted in G‐protein signaling bias at either D3R or D2R but not both, resulting in receptor‐selective bias. We also found that given the same ligand structure, chirality can confer subtype selectivity and promote G‐protein bias. Together, our novel bitopic D3R agonists based on PF592,379 scaffold provide novel tools to further probe unique pharmacology at D3R and evaluate the therapeutic potential of targeting D3R vs. D2R for PD. Support or Funding Information National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health