Synthesis and Characterization of Novel 2-Amino-3-benzoylthiophene Derivatives as Biased Allosteric Agonists and Modulators of the Adenosine A1 Receptor

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• 作者：Celine Valant ; Luigi Aurelio ; Shane M. Devine ; Trent D. Ashton ; Jonathan M. White ; Patrick M. Sexton ; Arthur Christopoulos ; Peter J. Scammells
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2367-2375
• 全文大小：393K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

A series of novel 2-amino-3-benzoylthiophenes (2A3BTs) were screened using a functional assay of A₁R mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in intact CHO cells to identify potential agonistic effects as well as the ability to allosterically modulate the activity of the orthosteric agonist, R-PIA. Two derivatives, 8h and 8i, differing only in terms of the absence or presence of an electron-withdrawing group on the benzoyl moiety of the 2A3BT scaffold, were identified as biased allosteric agonists and positive allosteric modulators of agonist function at the adenosine A₁ receptor (A₁R) in two different functional assays. Our findings indicate that subtle structural variations can promote functionally distinct receptor conformational states.