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Discovery and characterization of a G protein‐biased agonist of the D 2 dopamine receptor (662.7)
Author(s) -
Chun Lani,
Free R.,
Moritz Amy,
Conroy Jennie,
Meade Julie,
Xiao Jingbo,
Dulcey Andrés,
Vekariya Rakesh,
Ferrer Marc,
Javitch Jonathan,
Beuming Thijs,
Shi Lei,
Southall Noel,
Marugan Juan,
Aubé Jeff,
Frankowski Kevin,
Sibley David
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.662.7
Subject(s) - pharmacophore , arrestin , agonist , dopamine , g protein coupled receptor , receptor , functional selectivity , chemistry , signal transduction , microbiology and biotechnology , g protein , antagonist , signaling proteins , biology , computational biology , neuroscience , biochemistry
The D 2 dopamine receptor (D 2 R) can activate a spectrum of signaling cascades primarily through G proteins and β‐arrestin recruitment, making it an attractive target for the development of signaling biased ligands. Unlike dopamine, which simultaneously activates G proteins and recruits β‐arrestin, a biased ligand affects only one pathway, and the development of such ligands can allow for more fine‐tuned study of receptor signaling. Our lab has identified a compound (MLS1547) that is a highly efficacious agonist at D 2 R‐mediated G protein‐linked signaling, but it does not recruit β‐arrestin. Rather, this compound is an antagonist of D 2 R‐stimulated β‐arrestin‐mediated signaling. A number of structural analogs of MLS1547 were characterized for their signaling properties, which ranged from fully biased, partially biased, to unbiased. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure‐activity relationship of the functionally‐selective properties of these compounds. This, along with medicinal chemistry approaches, will allow for the identification of more potent G protein‐biased analogs of MLS1547 that will enable a highly targeted approach for investigating D 2 R signaling in vivo , and may eventually allow for selective treatment of disease symptoms associated with D 2 R dysfunction. Grant Funding Source : Supported by the NIH IRP.