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, a llyl, propyl, propargyl) or polar (CH2COOH, CH2CH2OH, CH2CN, CH2OCH3) substituents were tested at a 10 mM concentration. Many analog were as efficacious or only somewhat less efficacious than 10 mM caffeine. Ce rtain analogs with polar substituents had no effect. Disubstituted xan thines were less efficacious (theophylline, paraxanthine) than caffein e or were ineffective (theobromine). I-Propyl-3,7-dimethylxanthine (EC 50 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 th e latter was at least as efficacious.