Mesoionic xanthine analogues: antagonists of adenosine receptors

A variety of mesoionic xanthines including mesoionic thiazolo[3,2-alpha]pyrimidines, benzothiazolopyrimidines, and 1,3,4-thiadiazolo[3,2-alpha]pyrimidines were antagonists of A1-adenosine receptors (inhibition of binding of [3H]-cyclohexyladenosine) and A2-adenosine receptors (inhibition of 2-chloroadenosine-elicited accumulations of cyclic AMP) in brain tissue. Most of the compounds were less potent than theophylline and none were remarkably selective for A1- or A2-adenosine receptors. However, members of the thiadiazolopyrimidine class of mesoionics exhibited very low or no activity as antagonists of A2-adenosine receptors while exhibiting activity only 2-4-fold lower than that of theophylline at A1-adenosine receptors. Unlike the case for theophylline, the presence of a phenyl substituent in the five-membered ring did not enhance the potency of a mesoionic thiadiazolopyrimidine. The nature of the substituents on the mesoionic ring did not appear to have marked effects on potency unlike the marked effect of the nature of 1,3-substituents on activity of nonmesoionic xanthines. The benzothiazolo[3,2-alpha]pyrimidines were the most potent antagonists, being nearly as potent as theophylline at A1-adenosine receptors and somewhat more potent than theophylline at A2-adenosine receptors.