Potentiation of cADPR-induced Ca2+-release by methylxanthine analogues

Caffeine and other methylxanthines are known to induce Ca2+-release from in tracellular stores via the ryanodine receptor. In the present work, a range of caffeine analogues, in which methyl groups at the 1 and 7 positions wer e replaced with alkyl chains containing different functional groups (oxo, h ydroxyl, propargyl, ester, and acids), were synthesized. These compounds we re then screened for their ability to potentiate Ca2+-release induced by cA DPR (an endogenous modulator of ryanodine receptors) in sea urchin egg homo genates. Two of the synthesized methylxanthines, 1,3-dimethyl-7-(7-hydroxyo ctyl)xanthine (37) and 3-methyl-7-(7-oxooctyl)-1-propargylxanthine (66), we re shown to be more potent than caffeine in potentiating cADPR-induced Ca2-release, while 1,3-dimethyl-7-(5-ethylcarboxypentyl)xanthine (14) was show n to be more efficacious. The development of new methylxanthine analogues m ay lead to a better understanding of ryanodine receptor function and could possibly provide novel therapeutic agents.