N6‐Substituted 9‐methyladenines: A new class of adenosine receptor antagonists

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Abstract
A series of 15 N 6-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 N 6-R-[3H]phenylisopropyladenosine to A1-adenosine receptors in rat brain membranes. N 6 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 N 6 substituents on adenosine receptor activity of the 9-methyladenines are reminiscent of effects of N 6 substituents on activity of adenosine, suggesting that N 6 substituted 9-methyladenines bind to adenosine receptors in the same orientation as do N 6-substituted adenosines. N 6-Cyclopentyl-9-methyladenine with K i values at the A1 receptors of 1.3 μM (fat cells) and 0.5 μM (brain) is at least 100-fold more potent than 9-methyladenine (K i 100 μM, both receptors), while at the A2 receptors K B values of 5 μM (platelets) and 25 μM (PC12 cells) make it 5-fold more potent and equipotent, respectively, compared to 9-methyladenine (K B 24 μM, both receptors). N 6-Cyclopentyl and several other N 6-alkyl and N 6-cycloalkyl analogs are selective for A1 receptors while 9-methyladenine is the most A2 receptor selective antagonist. The N 6-R- and N 6-S-(1-phenyl-2-propyl)-9-methyladenines, analogous to N 6-R- and N 6-S-phenylisopropyladenosines, exhibit stereoselectivity at both A1 and A2 receptors. Marked differences in potency of certain N 6-substituted 9-methyladenines at the A1 receptors of human platelets and rat PC12 cells provide evidence that these are not identical receptors.