5'-C-Ethyl-tetrazolyl-N(6)-substituted adenosine and 2-chloro-adenosine derivatives as highly potent dual acting A1 adenosine receptor agonists and A3 adenosine receptor antagonists

J Med Chem. 2015 Mar 12;58(5):2560-6. doi: 10.1021/acs.jmedchem.5b00074. Epub 2015 Feb 27.

Abstract

A series of N(6)-substituted-5'-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2-chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA1AR agonists and hA3AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by N(6)-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA1- and hA3AR recognition and activation of this series of 5'-C-ethyl-tetrazolyl derivatives were explained.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / pharmacology*
  • Adenosine A1 Receptor Agonists / chemical synthesis
  • Adenosine A1 Receptor Agonists / pharmacology*
  • Adenosine A3 Receptor Antagonists / chemical synthesis
  • Adenosine A3 Receptor Antagonists / pharmacology*
  • Animals
  • CHO Cells
  • Computer Simulation
  • Cricetinae
  • Cricetulus
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Radioligand Assay
  • Receptor, Adenosine A1 / chemistry*
  • Receptor, Adenosine A3 / chemistry*
  • Structure-Activity Relationship

Substances

  • Adenosine A1 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Receptor, Adenosine A1
  • Receptor, Adenosine A3
  • Adenosine