Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

J Med Chem. 2016 Feb 11;59(3):947-64. doi: 10.1021/acs.jmedchem.5b01402. Epub 2016 Feb 1.


A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cyclopentanes / chemical synthesis
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Purinergic P1 Receptor Agonists / chemical synthesis
  • Purinergic P1 Receptor Agonists / chemistry
  • Purinergic P1 Receptor Agonists / pharmacology*
  • Receptor, Adenosine A1 / metabolism
  • Receptor, Adenosine A3 / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity / drug effects


  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclopentanes
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A1
  • Receptor, Adenosine A3
  • Adenosine