Selective Bronchodilators from 1-(5′-Oxohexyl)xanthines

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Abstract
A series of twenty one 1-(5′-oxohexyl)xanthines substituted with alkyl chains at the N 3 and N 7 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 N 3 position, but decreased by the N 7 alkylation. The positive chronotropic activities in the right atrium were increased by introduction of an n-propyl group at the N 3 position but decreased by substitution of longer alkyl chains, and the action on the heart was diminished by N 7 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 N 3 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 N 3 and N 7 positions diminished the potency for the right atrium in guinea-pigs. 3-n-Pentyl- and 7-methy]-3-n-pentyl-1-(5′-oxohexyl)xanthines showed much higher bronchoselectivity than oxpentifylline and theophylline.