title: Synthesis and cardiovascular activity of new 8-alkylamino-1,3-dimethyl-7-(2-hydroxy-3- piperazinopropyl)-3,7-dihydro-1H-purine-2,6-diones.
abstract: 7-{2-Hydroxy-3-[4-(2-phenoxyethyl)-piperazinyl-1-yl]-propyl}-1,3-di-methyl-3,7-dihydro-1H-purine-2,6-dione dihydrochloride (2), and several of its 8-alkylamino substituted derivatives (11-17) were synthesized and tested for electrocardiographic, antiarrhythmic and hypotensive activity. Also their alpha(1)- and alpha(2)-adrenoreceptor affinities were determined. It was found that compound 2, and its analogue 15 with 8-(2-morpholin-4-yl-ethylamino) substituent displayed a strong prophylactic antiarrhythmic activity in experimentally induced arrhythmia (LD50/ED50 = 54.9 and 55.0, respectively). The hypotensive activity was observed for 8-benzylamino (11) or 8-(pyridin-2-yl-methylamino) (12) analogues. All the new derivatives (11-17) and 2 showed a weak affinity for alpha1-(Ki = 0.225-1.400 microM) and alpha2-(Ki = 0.152-4.299 microM) receptors.
authors.affiliation: Department of Pharmaceutical Chemistry, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Chłoń-Rzepa
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Dorata
authors.initials: D
authors.lastname: Maciag
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects*; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D011485:Protein Binding; D011688:Purinones / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C515640:7-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazinyl-1-yl)propyl)-1,3-di-methyl-3,7-dihydro-1H-purine-2,6-dione dihydrochloride; D002317:Cardiovascular Agents; D010879:Piperazines; D011688:Purinones; D011942:Receptors, Adrenergic, alpha