TY - JOUR
T1 - Potentiation of cADPR-induced Ca2+-release by methylxanthine analogues
AU - Cavallaro, Rosaria A.
AU - Filocamo, Luigi
AU - Galuppi, Annamaria
AU - Galione, Antony
AU - Brufani, Mario
AU - Genazzani, Armando A.
PY - 1999/7/15
Y1 - 1999/7/15
N2 - Caffeine and other methylxanthines are known to induce Ca2+-release from intracellular stores via the ryanodine receptor. In the present work, a range of caffeine analogues, in which methyl groups at the 1 and 7 positions were replaced with alkyl chains containing different functional groups (oxo, hydroxyl, propargyl, ester, and acids), were synthesized. These compounds were then screened for their ability to potentiate Ca2+-release induced by cADPR (an endogenous modulator of ryanodine receptors) in sea urchin egg homogenates. Two of the synthesized methylxanthines, 1,3-dimethyl-7-(7- hydroxyoctyl)xanthine (37) and 3-methyl-7-(7-oxooctyl)-1-propargylxanthine (66), were shown to be more potent than caffeine in potentiating cADPR- induced Ca2+-release, while 1,3-dimethyl-7-(5-ethylcarboxypentyl)xanthine (14) was shown to be more efficacious. The development of new methylxanthine analogues may lead to a better understanding of ryanodine receptor function and could possibly provide novel therapeutic agents.
AB - Caffeine and other methylxanthines are known to induce Ca2+-release from intracellular stores via the ryanodine receptor. In the present work, a range of caffeine analogues, in which methyl groups at the 1 and 7 positions were replaced with alkyl chains containing different functional groups (oxo, hydroxyl, propargyl, ester, and acids), were synthesized. These compounds were then screened for their ability to potentiate Ca2+-release induced by cADPR (an endogenous modulator of ryanodine receptors) in sea urchin egg homogenates. Two of the synthesized methylxanthines, 1,3-dimethyl-7-(7- hydroxyoctyl)xanthine (37) and 3-methyl-7-(7-oxooctyl)-1-propargylxanthine (66), were shown to be more potent than caffeine in potentiating cADPR- induced Ca2+-release, while 1,3-dimethyl-7-(5-ethylcarboxypentyl)xanthine (14) was shown to be more efficacious. The development of new methylxanthine analogues may lead to a better understanding of ryanodine receptor function and could possibly provide novel therapeutic agents.
UR - http://www.scopus.com/inward/record.url?scp=0033566154&partnerID=8YFLogxK
U2 - 10.1021/jm980469t
DO - 10.1021/jm980469t
M3 - Article
SN - 0022-2623
VL - 42
SP - 2527
EP - 2534
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -