Synthesis and adenosine receptor affinity of a series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine.
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.
Harden
F A
FA
Division of Science and Technology, Griffith University, Brisbane, Queensland, Australia.
Quinn
R J
RJ
Scammells
P J
PJ
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000138:chemical synthesis / Q000187:drug effects / Q000378:metabolism*
D011983:Receptors, Purinergic; D006151:Guanosine; C022591:doridosine