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Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism.


ABSTRACT: The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or ?-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward ?-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus ?-arrestin recruitment in D2R-BRET functional assays.

SUBMITTER: Bonifazi A 

PROVIDER: S-EPMC7594663 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D<sub>2</sub> Receptor (D<sub>2</sub>R) Biased Agonism.

Bonifazi Alessandro A   Yano Hideaki H   Ellenberger Michael P MP   Muller Ludovic L   Kumar Vivek V   Zou Mu-Fa MF   Cai Ning Sheng NS   Guerrero Adrian M AM   Woods Amina S AS   Shi Lei L   Newman Amy Hauck AH  

Journal of medicinal chemistry 20170316 7


The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physioche  ...[more]

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