Synthesis and characterization of novel 2-amino-3-benzoylthiophene derivatives as biased allosteric agonists and modulators of the adenosine A(1) receptor

J Med Chem. 2012 Mar 8;55(5):2367-75. doi: 10.1021/jm201600e. Epub 2012 Feb 17.


A series of novel 2-amino-3-benzoylthiophenes (2A3BTs) were screened using a functional assay of A(1)R 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 A(1) receptor (A(1)R) in two different functional assays. Our findings indicate that subtle structural variations can promote functionally distinct receptor conformational states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A1 Receptor Agonists / chemical synthesis*
  • Adenosine A1 Receptor Agonists / chemistry
  • Adenosine A1 Receptor Agonists / pharmacology
  • Allosteric Regulation
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / biosynthesis
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Receptor, Adenosine A1 / metabolism*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology


  • (2-amino-5-methyl-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone
  • (2-amino-5-methyl-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone
  • Adenosine A1 Receptor Agonists
  • Receptor, Adenosine A1
  • Thiophenes
  • Cyclic AMP
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3