Novel and Potent Dopamine D 2 Receptor Go-Protein Biased Agonists.

Featured Paper of the Month – September 2019.

The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D₂ receptor (D₂R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D₂R agonists linking the D₂R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D₂R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D₂R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and β-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D₂Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.

Publication Information

Bonifazi, Alessandro; Yano, Hideaki; Guerrero, Adrian M; Kumar, Vivek; Hoffman, Alexander F; Lupica, Carl R; Shi, Lei; Newman, Amy Hauck

Novel and Potent Dopamine D2 Receptor Go-Protein Biased Agonists. Journal Article

In: ACS Pharmacol Transl Sci, vol. 2, no. 1, pp. 52–65, 2019, ISSN: 2575-9108 (Electronic); 2575-9108 (Linking).

Abstract | Links

@article{Bonifazi:2019aa,

title = {Novel and Potent Dopamine D2 Receptor Go-Protein Biased Agonists.},

author = {Alessandro Bonifazi and Hideaki Yano and Adrian M Guerrero and Vivek Kumar and Alexander F Hoffman and Carl R Lupica and Lei Shi and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30775693},

doi = {10.1021/acsptsci.8b00060},

issn = {2575-9108 (Electronic); 2575-9108 (Linking)},

year  = {2019},

date = {2019-02-08},

journal = {ACS Pharmacol Transl Sci},

volume = {2},

number = {1},

pages = {52--65},

address = {Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D2 receptor (D2R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D2R agonists linking the D2R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D2R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D2R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and beta-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D2Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}