title: Synthesis and evaluation of some xanthone derivatives for anti-arrhythmic, hypotensive properties and their affinity for adrenergic receptors.
abstract: A series of 2-, 4- or 2-methyl-6-substituted xanthone derivatives 8-17 containing selected piperazine moieties were synthesized and tested for their electrocardiographic, anti-arrhythmic, and antihypertensive activity, as well as for the alpha1- and beta1-adrenoceptor binding affinities. Of the newly synthesized derivatives, 2-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one dihydrochloride 9, 4-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one dihydrochloride 12, and 4-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethoxy)-9H-xanthen-9-one dihydrochloride 15 possessed significant anti-arrhythmic activity in the adrenaline-induced model of arrhythmia, with the ED50 values ranging 1.7-7.2 mg/kg. Compound 15 had the lowest ED50 value equaling 1.7 mg/kg, which was comparable with ED50 value of propranolol, which was used in this test as a reference compound. Compound 9 showed also the strongest hypotensive activity, which persisted for 60 minutes at the dose of 2.5 mg/kg. 2-(2-(4-(2-Phenoxyethyl)piperazin-1-yl)ethoxy)-9H-xanthen-9-one dihydrochloride 8 also significantly lowered blood pressure at a dose of 2.5 mg/kg but much weaker than compound 9. Binding studies are in agreement with our pharmacological results and could explain anti-arrhythmic effect of compound 15 and anti-arrhythmic and hypotensive effects of compounds 9 and 12.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland. hen.mar@interia.pl
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
authors.forename: Natalia
authors.initials: N
authors.lastname: Szkaradek
authors.forename: Monika
authors.initials: M
authors.lastname: Kubacka
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Marek
authors.initials: M
authors.lastname: Cegla
authors.forename: Edward
authors.initials: E
authors.lastname: Szneler
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D011941:Receptors, Adrenergic; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D044004:Xanthones