title: Pyrazolo[3,4-d]pyrimidines as adenosine antagonists.
abstract: A large number of nitrogen heterocycles structurally related to caffeine and theophylline have been tested for activity as adenosine antagonists. Preliminary screening, utilizing displacement of [3H]N6-phenylisopropyladenosine (PIA) binding to rat brain membranes, identified several pyrazolo[3,4-d]pyrimidines with potential antagonist activity. These were then tested for their ability to antagonize adenosine-stimulated adenylate cyclase of guinea-pig slices and to block adenosine receptors which mediate presynaptic inhibition of transmitter release from cholinergic nerves in guinea-pig ileum. Of several compounds found to have antagonist activity, one of these, 4,6-bis-alpha- carbamoylethylthio -1-phenylpyrazolo[3,4-d]pyrimidine ( DJB -KK) was approximately an order of magnitude more potent than theophylline in both tests. GTP greatly reduces the potency of purine agonists, but not antagonists, as inhibitors of [3H] PIA binding; the potency of the pyrazolo[3,4-d]pyrimidine compounds was not altered by GTP. The compounds have no significant activity against [3H]adenosine uptake or on the binding of ligands to muscarinic cholinergic, beta-adrenergic, GABA or L-glutamate receptors.
mesh_terms: D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000294:innervation; D007425:Intracellular Membranes / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D010660:Phenylisopropyladenosine / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011983:Receptors, Purinergic; D013574:Synaptosomes / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; D009538:Nicotine; D006160:Guanosine Triphosphate; D013806:Theophylline; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000241:Adenosine