Synthesis and adenosine receptor affinity of a series of pyrazolo[3,4-d]pyrimidine analogs of 1-methylisoguanosine

• Published in: Journal of medicinal chemistry Vol. 34; no. 9; pp. 2892 - 2898
• Main Authors: Harden, Fiona A, Quinn, Ronald J, Scammells, Peter J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.09.1991
• Subjects: Animals; Chemistry; Corpus Striatum - drug effects; Exact sciences and technology; Guanosine - analogs & derivatives; Guanosine - chemistry; Guanosine - pharmacology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Magnetic Resonance Spectroscopy; Male; Organic chemistry; Preparations and properties; Rats; Rats, Inbred Strains; Receptors, Purinergic - chemical synthesis; Receptors, Purinergic - drug effects; Receptors, Purinergic - metabolism; Nitrogen heterocycle; Animal; Bicyclic compound; A1 Adenosine receptor; Affinity; Ureas; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00113a031

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.