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 (EC50 50 microM and 60 microM, respectively), more potent than theophylline (300 microM). In guinea-pig isolated atria TC (30-50 microM) was able to antagonize R-PIA (a stable agonist on adenosine receptors) negative effect in not a clearly competitive way. Higher concentration (100 microM) began to reverse that inhibitory effect. In vitro Ki of TC and TT for A1 and A2 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 Ca2+ 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.