Synthesis and pharmacological characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activity

Bioorg Chem. 2016 Apr;65:26-37. doi: 10.1016/j.bioorg.2016.01.003. Epub 2016 Jan 21.

Abstract

The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the adenosine receptor (AR) binding affinities of the newly synthesized xanthines have also been studied. The compounds displayed moderate to potent binding affinities toward various adenosine receptor subtypes when evaluated through radioligand binding studies. However, most of the compounds showed the maximum affinity for the A2A subtype, some with high selectivity versus all other subtypes. Xanthine carboxylate amide 13b with a diethylaminoethylamino moiety at the para-position of the 8-phenylxanthine scaffold was identified as the most potent A2A adenosine receptor ligand with Ki=0.06μM. Similarly potent and highly A2A-selective are the isovanillin derivatives 16a and 16d. In addition, the newly synthesized xanthine derivatives showed good in vivo bronchospasmolytic activity when tested in guinea pigs.

Keywords: 8-Phenylxanthine carboxylate amides; Adenosine receptor ligands; Bronchospasmolytic agents; Partition coefficient.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerosols / chemistry
  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology*
  • Animals
  • Bronchial Spasm / drug therapy
  • CHO Cells
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Cells, Cultured
  • Cricetulus
  • Guinea Pigs
  • Histamine / chemistry
  • Humans
  • Ligands
  • Male
  • Receptor, Adenosine A2A / metabolism*
  • Structure-Activity Relationship
  • Xanthine / chemistry
  • Xanthine / pharmacology*

Substances

  • Aerosols
  • Amides
  • Carboxylic Acids
  • Ligands
  • Receptor, Adenosine A2A
  • Xanthine
  • Histamine