Synthesis and Biological Effects of a New Series of 2-Amino-3-Benzoylthiophenes as Allosteric ‎Enhancers of A1-Adenosine Receptor
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Original research
  • Abdel Naser Zaid
  • Pier Giovanni Baraldi
  • Ilaria Lampronti
  • Francesca Fruttarolo
  • Maria Giovanna Pavani
  • Mojgan Aghazadhe Tabrizi
  • John C Shryock
  • Edward Leung
  • Romeo Romagnoli

New derivatives of PD 81,723, an allosteric enhancer of agonist binding to the A1-adenosine receptor, have been synthesized and evaluated in an intact cell assay. Compounds 3a, 3o and 3p appeared to be more potent than PD 81,723 and at a concentration of 0.1 μM caused significant reductions of cAMP content of CHO cells expressing the human A1-adenosine receptor. Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration, whereas compounds 3c, 3g,3s and 4l appeared to be weak antagonists that are also allosteric enhancers at the higher concentration of 10 μM.

Adenosine is a ubiquitous autocoid with multiple effects on the human body. Adenosine can bind to four different P1-purinoreceptors (A1, A2A, A2B, A3) which belong to the broad group of receptors coupled to G-proteins and which modulate the activity of adenylate cyclase.1 A1-Adenosine receptors are found in many tissues including the heart, kidney, brain and spinal cord, adipose and thyroid tissues, lung, and immune system cells. In 1990, Bruns and co-workers2 and 3 reported that 2-amino-3-benzoylthiophene derivatives both enhanced the binding of agonists to the A1-adenosine receptor and (usually at higher concentrations) acted as competitive antagonists at these receptors. Among the synthesized compounds, PD 81,723 ((2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone) was identified as the compound with the best ratio of enhancement to antagonistic action at the A1-adenosine receptor.3 To study the role of various substitutions on the phenyl ring and the importance of the 4,5-dimethyl group on the thienyl ring, Baraldi4 and Ijzerman5 have described the synthesis and biological evaluation of mostly novel PD 81,723 analogues. The purpose of our investigation was to synthesize and evaluate a new series of derivatives of PD 81,723 and to establish the structural requirements and the structure–activity relationship for enhancement of the action of an agonist at the human A1-adenosine receptor.

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Bioorganic & Medicinal Chemistry Letters Volume 10, Issue 17, Pages 1953–1957
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