| Autor: |
Alessandro, Bonifazi, Hideaki, Yano, Michael P, Ellenberger, Ludovic, Muller, Vivek, Kumar, Mu-Fa, Zou, Ning Sheng, Cai, Adrian M, Guerrero, Amina S, Woods, Lei, Shi, Amy Hauck, Newman |
| Rok vydání: |
2017 |
| Předmět: |
|
| Zdroj: |
J Med Chem |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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