Structure-cardiovascular activity relationships in a group of new 8-alkylamino-1,3-dimethyl-7-(2-hydroxy-3-aminopropyl)-3,7-dihydro-1H-purine-2,6-d iones.

摘要

On the basis of our earlier studies in a group of 7,8-disubstituted derivatives of 1,3-dimetyl-3,7-dihydropurine-2,6-dione, a series of new 8-alkylamino-1,3-dimethyl-7-(2-hydroxy-3-aminopropyl)-3,7-dihydropurine-2,6-dione s (8-15) were synthesized and tested for their electrocardiographic, antiarrhythmic and hypotensive activity and for alpha(1)- and alpha(2)-adrenoreceptor affinities. Among the new derivatives, compounds with the 7-[2-hydroxy-3-(4-phenylpiperazine)-propyl] substituent (9-11) displayed prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia. Analogue 10 with the 8-(2-morpholin-4-yl)-ethylamino group was the most active (ED(50) = 3.9 mg/kg and TI = 59.8), which may indicate that this substituent is preferably important for the antiarrhythmic effect. Only compound 11 with the 8-(2-diethylamino)-ethylamino group significantly decreased the systolic (20.4-28.1%) and diastolic (23.4-33.2%) pressure, but this effect lasted for only 1-5 min. The pharmacologically active compounds 9-11 with the phenylpiperazine moiety showed affinity for alpha(1)-receptors (K(i) = 0.143-0.383 muM), but the other compounds were almost (12-15) or completely (8) inactive at this site. Compounds 9-11 and 13-15 displayed moderate to low affinity for alpha(2)-receptors (K(i) = 0.36-2.7 muM).