Open AccessNovel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism
Author(s) -
Alessandro Bonifazi,
Hideaki Yano,
Michael P. Ellenberger,
Ludovic Muller,
Vivek Kumar,
MuFa Zou,
Ning Cai,
Adrian M. Guerrero,
Amina S. Woods,
Lei Shi,
Amy Hauck Newman
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.6b01875
Subject(s) - pharmacophore , chemistry , bivalent (engine) , agonist , intrinsic activity , stereochemistry , receptor , structure–activity relationship , arrestin , g protein coupled receptor , in vitro , biochemistry , organic chemistry , metal
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, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G i/o -proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D 2 G-protein biased agonism with an EC 50 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 β-arrestin recruitment in D 2 R-BRET functional assays.