ALKYLXANTHINES - INHIBITION OF ADENOSINE-ELICITED ACCUMULATION OF CYCLIC-AMP IN BRAIN-SLICES AND OF BRAIN PHOSPHODIESTERASE ACTIVITY

A series of 1, 3-dialkylxanthines was examined as antagonists of adenosine-induced accumulation of cyclic AMP in guinea pig cerebral cortical slices and as inhibitors of brain phosphodiesterases. The order of potency as adenosine-antagonists was: 8-phenyltheophylline (IC50 6 μM) > 1, 3-dibutylxanthine (IC50 30 μM), 1, 3-dipropylxanthine > theophylline (IC50 60 μM), 3-isobutyl-1-methylxanthine (IBMX), 1, 3, 7-triethylxanthine > 7-benzyl IBMX (IC50 100 μM), 8-methyl IBMX > 7-benzyl-8-bromo IBMX, 9-methyl IBMX, 8-bromo IBMX, 1-isoamyl-3-isobutylxanthine. The order of potency as inhibitors of brain calcium-dependent phosphodiesterase was: 7-benzyl IBMX (IC50 1.5 μM), 7-benzyl-8-bromo IBMX > 8-methyl IBMX (IC50 4.5 μM) > IBMX (IC50 7.5 μM), 8-bromo IBMX > 9-methyl IBMX (IC50 40 μM), 1, 3, 7-triethylxanthine > 1, 3-dibutylxanthine (IC50 100 μM), 1-isoamyl-3-isobutylxanthine > theophylline. 8-Phenyltheophylline and 1, 3-dibutylxanthine represented potent adenosine-antagonists with relatively low activity as phosphodiesterase inhibitors whereas 7-benzyl IBMX and 7-benzyl-8-bromo-IBMX were potent inhibitors of the calcium-dependent phosphodiesterase with relatively low activity as adenosine-antagonists. None of the compounds were potent inhibitors of the brain calcium-independent phosphodiesterase, although 1-isoamyl-3-isobutylxanthine might prove useful as an inhibitor of this enzyme because of its very low activity as an adenosine-antagonist. © 1979.