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Novel sumanirole bivalent analogues as potent dopamine D2 receptor Go‐protein biased agonists
Author(s) -
Yano Hideaki,
Bonifazi Alessandro,
Hoffman Alexander F,
Lupica Carl R,
Shi Lei R,
Newman Amy H
Publication year - 2019
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.2019.33.1_supplement.667.11
Subject(s) - g protein coupled inwardly rectifying potassium channel , agonist , dopamine receptor d2 , pharmacophore , chemistry , dopaminergic , g protein coupled receptor , bivalent (engine) , dopamine , pharmacology , neuroscience , g protein , receptor , biochemistry , biology , organic chemistry , metal
The dopamine D2 receptor (D2R) is a major target for therapeutic development of treatments for neuropsychiatric disorders. In particular, D2R agonists have been used for neurological disorders such as restless leg syndrome and Parkinson's Disease. However, current D2R agonist pharmacotherapies have drawbacks including the development of tolerance and other adverse side‐effects. To potentially improve D2R agonist‐based medications, we have designed bivalent ligands that have two pharmacophores tethered by a link. This strategy aims to improve selectivity, affinity, and cell signaling activation bias. Indeed, it has been demonstrated that the secondary pharmacophore plays a key role in inducing activation bias towards either G protein, or β‐arrestin pathways. Here we characterized a series of bivalent orthosteric‐arthosteric heteroaryl pharmacophores with assorted linkers and compared them with the potent orthosteric D2R‐selective agonist, sumanirole. Several bivalent analogues demonstrated modest increases in D2R affinity compared to sumanirole. D2R functional assays using bioluminescence resonance energy transfer (BRET) showed improved efficacy and potency for G protein coupling, but substantially diminished efficacy and potency for β‐arrestin recruitment. Analysis using an operational model of bias revealed significant G‐protein activation bias (>1000‐fold). Further, several compounds exhibited a G protein subtype (GoA over Gi1) activation bias. Finally, D2R‐mediated, G protein‐coupled inwardly‐rectifying potassium channel (GIRK) activity was measured in midbrain slices using electrophysiology. Recordings from D2R‐expressing dopaminergic cells in the ventral tegmental area confirmed prolonged GIRK activation by the biased bivalent compounds, compared to dopamine or sumanirole. Our novel sumanirole bivalent analogues demonstrate a proof of concept for G protein activation bias and thus may lead to D2R agonist therapeutics with reduced tolerance and improved efficacy. With these novel tools, the preferential targeting and activation of Go‐proteins, the most predominant Gi‐like protein family in the brain, are now conceivable in animal models. This advance may aid in treatments of basal ganglia disorders with reductions in untoward side‐effects in humans. Support or Funding Information Work was supported by the Intramural funds of the National Institute on Drug Abuse This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .