Pharmacological effects and binding studies of new methylxanthine thioderivatives

Abstract

The effects of two methylxanthine derivatives, 6-thiocaffeine (TC) and 6-thiotheophylline (TT), were investigated in different in vitro and in vivo conditions. On guinea-pig isolated trachea, both TC and TT showed a relaxant effect (EC 50 50 μ m and 60 μ m, respectively), more potent than theophylline (300 μ m). In guinea-pig isolated atria TC (30–50 μm) was able to antagonize R-PIA (a stable agonist on adenosine receptors) negative effect in not a clearly competitive way. Higher concentration (100 μ m) began to reverse that inhibitory effect. In vitro K i of TC and TT for A 1 and A 2 adenosine receptors was intermediate in comparison to caffeine and theophylline. On the contrary, the two thioderivatives showed a higher affinity for [ 3H]-nitrendipine binding sites, in comparison to the original methylxanthines. All these data suggest a complex mechanism of action, probably at the level of adenosine extracellular receptors and L-type Ca 2+ channels. In vivo experiments in mice provided evidence for a lack of CNS stimulant effects, but a loss of motor coordination was observed. Both thioderivatives showed a reduced acute toxicity. These data can be useful for the development of drugs for the therapy of asthma with reduced side effects.