N6,9-Disubstituted Adenines: Potent, Selective Antagonists at the A1 Adenosine Receptor

Article abstract of DOI:10.1021/jm00113a029

N⁶-Substituted 9-methyladenines are potent antagonists of the activation of A₁ adenosine receptors.The present study assessed the effect of N⁶ and N-9-substituents on the binding of adenines to the A₁ and A₂ receptors, respectively, of rat brain cortex and striatum and also on the antagonism of the A₂ receptor mediated stimulation of the adenylate cyclase of PC12 cells by N-ethyladenosine-5'-uronamide.The potency ranking of 9-substituted adenines varied directly with the hydrophobicity of the substituent: cyclopentyl > phenyl > tetrahydrofuryl > ethyl > methyl > 2-hydroxyethyl.The 9-substituted adenines showed little selectivity for either receptor and the R enantiomer of N⁶-(1-phenyl-2-propyl)-9-methyladenine was only 4-fold more potent than the S enantiomer at the A₁ receptor.An N⁶-cyclopentyl substituent increased potency at the A₁ receptor and decreased potency at the A₂ receptor, resulting in selectivity for the A₁ receptor of up to 39-fold.The N⁶-cyclopentyl group completely overshadowed the effect of the hydrophobicity of the 9-substituent.A 2-chloro substituent did not alter the potency of an N⁶-substituted 9-methyladenine.