Design and characterization of optimized adenosine A₂A/A₁ receptor antagonists for the treatment of Parkinson's disease

J Med Chem. 2012 Feb 9;55(3):1402-17. doi: 10.1021/jm201640m. Epub 2012 Jan 26.


The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

MeSH terms

  • Adenosine A1 Receptor Antagonists / chemical synthesis*
  • Adenosine A1 Receptor Antagonists / pharmacokinetics
  • Adenosine A1 Receptor Antagonists / pharmacology
  • Adenosine A2 Receptor Antagonists / chemical synthesis*
  • Adenosine A2 Receptor Antagonists / pharmacokinetics
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Administration, Oral
  • Animals
  • Drug Design
  • Female
  • Indenes / chemical synthesis*
  • Indenes / pharmacokinetics
  • Indenes / pharmacology
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A2A / metabolism*
  • Structure-Activity Relationship


  • 2-amino-8-(2-morpholinoethoxy)-4-phenyl-5H-indeno(1,2-d)pyrimidin-5-one
  • 2-amino-8-(4-methylpiperazine-1-carbonyl)-4-phenyl-5H-indeno(1,2-d)pyrimidin-5-one
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Indenes
  • Pyrimidines
  • Receptor, Adenosine A2A