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2017 |
Bonifazi, Alessandro; Yano, Hideaki; Ellenberger, Michael P; Muller, Ludovic; Kumar, Vivek; Zou, Mu-Fa; Cai, Ning Sheng; Guerrero, Adrian M; Woods, Amina S; Shi, Lei; Newman, Amy Hauck Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism. Journal Article In: J Med Chem, vol. 60, no. 7, pp. 2890–2907, 2017, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @article{Bonifazi:2017aab, 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 beta-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 beta-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 beta-arrestin recruitment in D2R-BRET functional assays. |