Adenosine receptor binding: Structure-activity analysis generates extremely potent xanthine antagonists

Structure-activity analysis of alkylxanthine derivatives at adenosine receptor binding sites has been employed to design more potent adenosine receptor antagonists. Receptor affinities of xanthines were determined by measuring inhibition of the binding of N⁶-[³H]cyclohexyladenosine to bovine brain membranes. 1,3-Dipropyl substitutions enhance potency compared to the 1,3-dimethyl substitution in theophylline. An 8-phenyl substituent produces a considerable increase in potency, which is augmented by certain para substitutions on the 8-phenyl ring. Combining an ortho amino with a para-chloro substituent on the 8-phenyl ring affords further increases in potency. Combining all of these substituents results in 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine, a compound of extraordinary receptor affinity, with a K(i) for adenosine A₁ receptors of 22 pM. It is 4,000,000 times more potent than xanthine itself and 70,000 times more potent than theophylline.