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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.

Original publication

DOI

10.1021/jm980469t

Type

Journal article

Journal

J Med Chem

Publication Date

15/07/1999

Volume

42

Pages

2527 - 2534

Keywords

Adenosine Diphosphate Ribose, Animals, Caffeine, Calcium, Cyclic ADP-Ribose, Drug Evaluation, Preclinical, In Vitro Techniques, Ovum, Ryanodine Receptor Calcium Release Channel, Sea Urchins, Structure-Activity Relationship, Xanthines