title: Synthesis and preliminary evaluation of pharmacological properties of some piperazine derivatives of xanthone.
abstract: A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α(1)-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals' models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED(50) value of 0.69 mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED(50) = 0.88 mg/kg and 0.89 mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol. Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland. nszkarad@cm-uj.krakow.pl
authors.forename: Natalia
authors.initials: N
authors.lastname: Szkaradek
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.forename: Karolina
authors.initials: K
authors.lastname: Pytka
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.forename: Marek
authors.initials: M
authors.lastname: Cegła
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D011941:Receptors, Adrenergic; D044004:Xanthones; D000077489:Piperazine; C009689:xanthone