Synthesis and Adenosine Receptor Affinity of a Series of pyrazolo[3,4-d]pyrimidine Analogues of 1-methylisoguanosine

J Med Chem. 1991 Sep;34(9):2892-8. doi: 10.1021/jm00113a031.

Abstract

Pyrazolo[3,4-d]pyrimidines are pyrazolo analogues of purines. They have been shown to be a general class of compounds which exhibit A1 adenosine receptor affinity. Two series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine have been synthesized. The first involved substitution of the N1-position while the second involved substitution of the N5-position. Both alkyl and aryl substituents were examined. All compounds were tested for A1 adenosine receptor affinity by using a (R)-[3H]-N6-(phenylisopropyl)adenosine binding assay. The 3-chlorophenyl group showed the greatest activity in the N1-position and the butyl group produced the greatest activity in the N5-position. Combination of the best substituent in each of these positions enhanced the overall activity. The most potent compound was 4-amino-5-N-butyl-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6(5H)- one with an IC50 of 6.4 x 10(-6) M. Selectivity at the receptor subclasses was examined by performing an A2 adenosine receptor affinity assay with [3H]CGS 21680. This series of compounds were slightly less potent at A2 receptors. 4-Amino-5-N-butyl-1-(3-chlorophenyl-1H-pyrazolo[3,4-d]pyrimidin-6(5H)-one was the most potent compound with an IC50 of 19.2 x 10(-6) M.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Guanosine / analogs & derivatives*
  • Guanosine / chemistry
  • Guanosine / pharmacology
  • Magnetic Resonance Spectroscopy
  • Male
  • Rats
  • Rats, Inbred Strains
  • Receptors, Purinergic / chemical synthesis
  • Receptors, Purinergic / drug effects
  • Receptors, Purinergic / metabolism*

Substances

  • Receptors, Purinergic
  • Guanosine
  • doridosine