ACTIVITIES OF CAFFEINE, THEOPHYLLINE, AND ENPROFYLLINE ANALOGS AS TRACHEAL RELAXANTS

A variety of xanthines cause tracheal relaxation, an activity predictive of antiasthmatic potential. Structural analogs of caffeine, theophylline, and enprofylline were examined for their abilities to relax carbamylcholine-stimulated guinea pig trachea in vitro. All caffeine analogs tested were more potent than caffeine (ec50 = 551 ± 81μM) except the 8-p-sulfophenyl analog. 1,3,7-Tripropylxanthine and 1,3,7-tripropargylxanthine were among the more potent analogs with ec50 values of 12 ± 1.3 and 65 ± 11 μM respectively. Increasing the polarity at the 1- or 3-position by substituting a propargyl group for an n-propyl group decreased relaxant activity, an effect not observed at the 7-position. The 8-cyclohexyl-, 8-cyclopentyl- and 8-phenyl-derivatives of caffeine were relatively potent (ec50 = approximately 75 μM). The theophylline analog 1,3-di-n-propylxanthine was approximately two times more active than theophylline (ec50 = 162 ± 17 μM). 3-Isobutyl-1-methylxanthine (ec50 = 7.1 ± 1.8 μM) and 1-isoamyl-3-isobutylxanthine (ec50 = 37 ± 4.2 μM) were among the most potent tracheal relaxants. The 8-substituted theophylline analogs were weak or inactive relaxants except for 8-cyclopentyl- and 8-cyclohexyltheophylline, which were more potent or as potent as theophylline. In contrast to enprofylline (ec50 = 56 ± 9 μM), 8-substituted enprofylline analogs were weak or inactive as relaxants with the exception of the 8-cyclohexyl analog. The potency of xanthines as tracheal relaxants was unrelated to potency as adenosine receptor antagonists and may reflect activity as phosphodiesterase inhibitors. © 1990.