New derivatives of methyl-xanthines: effect of thiocaffeine thiotheophylline and 8-phenyltheophylline on lipolysis and on phosphodiesterase activities.

The effects of some old and new methylxanthines and 6-thioxanthines, i.e. theophylline (TH), caffeine (CAFF), thiotheophyl line (S-TH), thiocaffeine (S-CAFF), 8-phenyltheophylline (8-PT), 3-isobutyl-1-methyl-xanthine (IBMX) were compared at the level of adipose tissue on spontaneous and norepinephrine-induced lipolysis as well as on fat cell phosphodiesterases. These agents stimulated lipolysis. 8-PT was the most potent; thiocaffeine and thiotheophylline the least potent; IBMX and theophylline had intermediate potencies. The order of potency of the same drugs in potentiating norepinephrine-stimulated lipolysis was: IBMX greater than 8-PT greater than S-CAFF greater than greater than S-TH greater than CAFF greater than TH. The rank order of potency to inhibit cAMP phosphodiesterases was: IBMX greater than S-TH and S-CAFF greater than TH much greater than 8-PT (uneffective). Thus (a) thiocaffeine and thiotheophylline were more potent than the parent compound theophylline in inhibiting cAMP-PDE, although their per se stimulating effect on lipolysis was much lower. This indicates that in the thioxanthines the stimulus per se on lipolysis can be dissociated from their effectiveness as inhibitors of PDE. (b) In contrast, 8-PT (a blocker of adenosine receptors) has a potent lipolytic action per se and a potentiating effect on norepinephrine-induced lipolysis, even if deprived of effect on PDE. This indicates that the potentiating power of methylxanthines on norepinephrine-stimulated lipolysis is not strictly dependent on their anti-PDE activities. These results suggest that in adipose tissue (more similar than adipocytes to the in vivo conditions) the anti-adenosine potency of methylxanthines is the prominent factor in stimulating basal lipolysis. Both anti-adenosine and anti-PDE activities are involved in modulating hormone-induced lipolysis.