Stimulation of calcium release by caffeine analogs in pheochromocytoma cells

Caffeine (EC50 approximately 20 mM) causes a maximal 400% increase in intracellular calcium ion concentration ([Ca2+]i) in pheochromocytoma PC12 cells. A range of caffeine analogs in which methyl groups at the 1, 3, and 7 positions were replaced with relatively nonpolar (ethyl, allyl, propyl, propargyl) or polar (CH2COOH, CH2CH2OH, CH2CN, CH2OCH3) substituents were tested at a 10 mM concentration. Many analogs were as efficacious or only somewhat less efficacious than 10 mM caffeine. Certain analogs with polar substituents had no effect. Disubstituted xanthines were less efficacious (theophylline, paraxanthine) than caffeine or were ineffective (theobromine). 1-Propyl-3,7-dimethylxanthine (EC50 4 mM) and 1-propargyl-3,7-dimethylxanthine (EC50 5 mM) were several-fold more potent than caffeine in causing elevation of [Ca2+]i and the latter was at least as efficacious.