Caffeine analogs: effects on ryanodine-sensitive calcium-release channels and GABAA receptors.

1. Caffeine at 0.3-10 mM enhanced the binding of [3H]ryanodine to calcium-release channels of rabbit muscle sarcoplasmic reticulum. A variety of other xanthines were as efficacious as caffeine or nearly so, but none appeared markedly more potent. 2. Caffeine at 1 mM markedly inhibited binding of [3H]diazepam to GABAA receptors in rat cerebral cortical membranes. 3. Other xanthines also inhibited binding with certain dimethylpropargylxanthines being nearly fivefold more potent than caffeine. 4. Caffeine at 1 mM stimulated binding of [35S]TBPS to GABAA receptors as did certain other xanthines. 5. The dimethylpropargylxanthines had little effect. 1,3-Dipropyl-8-cyclopentylxanthine at 100 microM had no effect on [3H]diazepam binding, but markedly inhibited [35S]TBPS binding. 6. Structure-activity relationships for xanthines do differ for calcium-release channels and and for different sites on GABAA receptors, but no highly selective lead compounds were identified.