Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A₂A and A₃ adenosine receptor ligands

J Med Chem. 2012 Jan 12;55(1):342-56. doi: 10.1021/jm201229j. Epub 2011 Dec 28.

Abstract

Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis*
  • Adenosine / pharmacology
  • Adenosine A2 Receptor Agonists / chemical synthesis*
  • Adenosine A2 Receptor Agonists / pharmacology
  • Adenosine A3 Receptor Antagonists / chemical synthesis*
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / biosynthesis
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Male
  • Models, Molecular
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A3 / metabolism*
  • Receptors, Adenosine A2 / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacology

Substances

  • 2-(6-amino-2-(hex-1-enyl)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol
  • 2-(6-amino-2-(hex-1-ynyl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol
  • Adenosine A2 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Anti-Inflammatory Agents, Non-Steroidal
  • Ligands
  • Receptor, Adenosine A3
  • Receptors, Adenosine A2
  • Thiophenes
  • Cyclic AMP
  • Adenosine