Structure-functional selectivity relationship studies of beta-arrestin-biased dopamine D(2) receptor agonists.

Article Details

Citation

Chen X, Sassano MF, Zheng L, Setola V, Chen M, Bai X, Frye SV, Wetsel WC, Roth BL, Jin J

Structure-functional selectivity relationship studies of beta-arrestin-biased dopamine D(2) receptor agonists.

J Med Chem. 2012 Aug 23;55(16):7141-53. doi: 10.1021/jm300603y. Epub 2012 Aug 13.

PubMed ID
22845053 [ View in PubMed
]
Abstract

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first beta-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these beta-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AripiprazoleDopamine D2 receptorEC 50 (nM)1N/AN/ADetails
AripiprazoleDopamine D2 receptorEC 50 (nM)4N/AN/ADetails
AripiprazoleDopamine D2 receptorKi (nM)3.9N/AN/ADetails