title: N6-substituted 9-methyladenines: a new class of adenosine receptor antagonists.
abstract: A series of 15 N6-substituted 9-methyladenines have been assessed as antagonists of A2-adenosine receptor-mediated stimulation of adenylate cyclase in membranes of human platelets and rat PC12 cells and of A1-adenosine receptor-mediated inhibition of adenylate cyclases in membranes of rat fat cells and as inhibitors of binding of N6-R-[3H]phenylisopropyladenosine to A1-adenosine receptors in rat brain membranes. N6 substitution can markedly increase the potency of 9-methyladenine at A1 receptors, while having lesser effects or even decreasing potency at A2 receptors. Effects of N6 substituents on adenosine receptor activity of the 9-methyladenines are reminiscent of effects of N6 substituents on activity of adenosine, suggesting that N6 substituted 9-methyladenines bind to adenosine receptors in the same orientation as do N6-substituted adenosines. N6-Cyclopentyl-9-methyladenine with Ki values at the A1 receptors of 1.3 microM (fat cells) and 0.5 microM (brain) is at least 100-fold more potent than 9-methyladenine (Ki 100 microM, both receptors), while at the A2 receptors KB values of 5 microM (platelets) and 25 microM (PC12 cells) make it 5-fold more potent and equipotent, respectively, compared to 9-methyladenine (KB 24 microM, both receptors). N6-Cyclopentyl and several other N6-alkyl and N6-cycloalkyl analogs are selective for A1 receptors while 9-methyladenine is the most A2 receptor selective antagonist. The N6-R- and N6-S-(1-phenyl-2-propyl)-9-methyladenines, analogous to N6-R- and N6-S-phenylisopropyladenosines, exhibit stereoselectivity at both A1 and A2 receptors. Marked differences in potency of certain N6-substituted 9-methyladenines at the A2 receptors of human platelets and rat PC12 cells provide evidence that these are not identical receptors.
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology; D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D010673:Pheochromocytoma / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000502:physiology
chemical_list: D011983:Receptors, Purinergic; C013115:9-methyladenine; D000262:Adenylyl Cyclases; D000225:Adenine