Selective bronchodilators from 1-(5'-oxohexyl)xanthines

A series of twenty one 1-(5'-oxohexyl)xanthines substituted with alkyl chains at the N3 and N7 positions of the xanthine nucleus were prepared and their relaxant activity in guinea-pig isolated tracheal muscle and positive chronotropic activity in isolated right atrium of guinea-pig were compared. The tracheal relaxant activities were markedly increased with alkyl chain length at the N3 position, but decreased by the N7 alkylation. The positive chronotropic activities in the right atrium were increased by introduction of an n-propyl group at the N3 position but decreased by substitution of longer alkyl chains, and the action on the heart was diminished by N7 substitution. The activities of compounds on cAMP-phosphodiesterase (PDE) and binding of [3H]8-cyclopentyl-1,3-dipropylxanthine were measured in the homogenate of tracheal muscle and the membrane preparation of cerebral cortex, respectively. No relationship among tracheal muscle relaxant activity, cAMP-PDE inhibitory activity and adenosine antagonism of these xanthines was observed, and other action mechanisms should be considered for their relaxant activities. This study indicated that N3 alkylation is important for the selectivity for tracheal muscle, while the introduction of long alkyl chains such as n-butyl and n-pentyl groups at the N3 and N7 positions diminished the potency for the right atrium in guinea-pigs. 3-n-Pentyl- and 7-methyl-3-n-pentyl-1-(5'-oxohexyl)xanthines showed much higher bronchoselectivity than oxpentifylline and theophylline.