Potentiation of cADPR-induced Ca(2+)-release by methylxanthine analogues.
Caffeine and other methylxanthines are known to induce Ca(2+)-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 Ca(2+)-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 Ca(2+)-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.
Department of Biochemical Sciences, University La Sapienza, Via degli Apuli 9, 00185 Rome, Italy.
R A
RA
Cavallaro
L
L
Filocamo
A
A
Galuppi
A
A
Galione
M
M
Brufani
A A
AA
Genazzani
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D010063:Ovum / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects; D012617:Sea Urchins; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C120304:1,3-dimethyl-7-(5-ethylcarboxypentyl)xanthine; C120305:1,3-dimethyl-7-(7-hydroxyoctyl)xanthine; C120306:3-methyl-7-(7-oxooctyl)-1-propargylxanthine; D019837:Ryanodine Receptor Calcium Release Channel; D014970:Xanthines; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D002110:Caffeine; D002118:Calcium