BRONCHODILATOR ACTIVITY OF XANTHINE DERIVATIVES SUBSTITUTED WITH FUNCTIONAL-GROUPS AT THE 1-POSITION OR 7-POSITION

Xanthine derivatives with several functional groups at the 1- or 7-pos ition were synthesized, and their pharmacological activities in guinea pigs were studied. In general, the in vitro tracheal relaxant action and positive chronotropic action of 3-propylxanthines were increased b y substitutions with nonpolar functional groups at the 1-position, but decreased by any substitution at the 7-position. On the other hand, b ecause positive chronotropic actions of substituents with allyl, amino alkyl, alkoxyalkyl, and normal alkyl groups were much less than trache al muscle relaxant action, these compounds had high tracheal selectivi ty. The selectivity for tracheal muscle became very high with substitu tions of 3'-butenyl, (dimethylamino)ethyl, 2'-ethoxyethyl, 3'-methoxyp ropyl, and n-propyl groups at the 1-position and of 2'-ethoxyethyl, 2' -oxopropyl, and n-propyl groups at the 7-position, compared with theop hylline and the corresponding unsubstituted xanthines, 3-propylxanthin e and 1-methyl-3-propylxanthine. When compounds were intraduodenally a dministered to the guina pig, 1-(2'-ethoxyethyl)-, 1-(3'-methoxypropyl )-, 1-(3'-butenyl)-, and 1-[(dimethylamino)ethyl]-3-propylxanthines, 1 -methyl-7-(2'-oxopropyl)-3-propylxanthine, and denbufylline (1,3-di-n- butyl-7-(2'-oxopropyl)xanthine) effectively inhibited the acetylcholin e-induced bronchospasm without heart stimulation or central nervous sy stem-stimulation at the effective dosage range. Particularly, the bron chodilatory effect of 1-(2'-ethoxyethyl)-3-propylxanthine was much str onger and more continuous than those of theophylline and pentoxifyllin e. On the other hand, there were certain relationships among the in vi tro tracheal relaxant activities of these compounds, their affinities for adenosine (A1) receptors in the brain membrane, and their inhibiti on of cyclic AMP-phosphodiesterase (PDE) in the tracheal muscle. The a ffinity for A2 receptors of these compounds was very low or negligible . This suggests that both the action on A1 receptors or interaction wi th adenosine and the cyclic AMP-PDE inhibitory activity contribute to the bronchodilator action of 1- and 7-substituted xanthines. This stud y indicates that the substitutions with none or low polar functional g roups at the 1-position could improve the selectivity and duration of the bronchodilator effects of xanthines.