G protein-coupled receptors (GPCRs) signal not only via canonical pathways involving heterotrimeric large G proteins, but also via non-canonical G protein-independent interactions with other signaling proteins including β-arrestins. Functional selectivity (also known as signaling bias) refers to the process by which GPCR ligands differentially modulate canonical and non-canonical signal transduction pathways. Functionally selective ligands of GPCRs would be extremely useful for elucidating the key signal transduction pathways essential for both the therapeutic actions and side-effects of drugs. However, very few such ligands have been created and very little purposeful attention has been devoted to studying what we term: “structure-functional selectivity relationships” (SFSR). To discover functionally selective ligands of dopamine D2 receptors (D2R), we selected aripiprazole, an FDA-approved antipsychotic drug, as the starting point of our SFSR studies and extensively investigated multiple regions of the aripiprazole scaffold. In total, we synthesized ca. 400 novel compounds, which were evaluated in D2R binding, Gi-mediated cAMP accumulation, β-arrestin-2 translocation Tango assays, GPCR selectivity, mouse PK, and behavioral studies in both wild-type (WT) and β-arrestin-2 knockout (β-ARR2 KO) mice. Through these comprehensive SFSR studies, we discovered a number of extremely β-arrestin-biased D2R agonists (Allen et al., 2011; Chen et al., 2012; manuscripts in preparation). These compounds were simultaneously full or partial agonists for D2R/β-arrestin-2 interactions and inactive at Gi-regulated cAMP production with excellent mouse PK parameters including high oral bioavailability and CNS penetration. Importantly, these β-arrestin-biased D2R agonists displayed robust antipsychotic drug-like activities in WT mice, but the significant antipsychotic drug-like activities were either completely abolished or significantly attenuated in β-ARR2 KO mice, suggesting that β-arrestin recruitment and signaling can be a significant contributor to antipsychotic efficacy. In addition, we discovered an extremely Gi-biased D2R agonist (manuscript in preparation). The discovery and in vitro and in vivo characterization of these functionally selective D2R agonists will be presented. Supported by NIH (grant number: U19MH82441)

Discovery of functionally selective ligands of fopamine D2receptors

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.