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-diones

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-diones (8-15) were synthesized and tested for their electrocardiographic,antiarrhythmic and hypotensive activity and for 1- and 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 1-receptors (ki = 0.143-0.383 μm),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 2-receptors (ki = 0.36-2.7 μm). copyright © 2011 by institute of pharmacology polish academy of sciences.