Allosteric modulation of the adenosine A(1) receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding

J Med Chem. 1999 Sep 9;42(18):3629-35. doi: 10.1021/jm991051d.


Novel allosteric enhancers of agonist binding to the rat adenosine A(1) receptor are described. The lead compound for the new series was PD 81,723 ((2-amino-4, 5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]methanone), a compound previously reported by Bruns and co-workers (Mol. Pharmacol. 1990, 38, 950-958). The 4,5-dimethyl group and the benzoyl moiety were targets for further modifications, leading to series of 4, 5-dialkyl (12a-g), of tetrahydrobenzo (12h-u), and of tetrahydropyridine (13a-g) derivatives. A number of compounds, in particular 12b, 12e, 12j, 12n, and 12u, proved superior to PD 81,723. Their EC(50) values for enhancing the binding of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine to the receptor were lower, and/or their antagonistic activity on the adenosine A(1) receptor was shown to be diminished.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Allosteric Regulation / drug effects
  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Purinergic P1 Receptor Agonists*
  • Purinergic P1 Receptor Antagonists
  • Rats
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacology
  • Xanthines / metabolism


  • Purinergic P1 Receptor Agonists
  • Purinergic P1 Receptor Antagonists
  • Thiophenes
  • Xanthines
  • PD 81723
  • N(6)-cyclopentyladenosine
  • 1,3-dipropyl-8-cyclopentylxanthine
  • Adenosine