title: Design, synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy-propyl]-3,3-diphenylpyrrolidin-2-one derivatives with antiarrhythmic, antihypertensive, and alpha-adrenolytic activity.
abstract: A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha(1)- and alpha(2)-adrenoceptors (ARs), as well as their antiarrhythmic, and antihypertensive activities. The highest affinity for the alpha(1)-AR was displayed by 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pK(i)=7.28. The highest affinity for the alpha(2)-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pK(i)=6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for alpha(1B)- and alpha(1D)-AR, which gave pA(2) alpha(1B)=6.55 and pA(2) alpha(1D)=7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50) value was 1.1mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5-5.0mg/kg (i.v.) and their hypotensive effects lasted for longer than 1h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both alpha(1)- and alpha(2)-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure-activity relationship, a preliminary molecular modeling study was undertaken.
authors.affiliation: Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Faculty of Pharmacy, 30-688 Kraków, Poland. mfkkulig@cyf.kr.edu.pl
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.forename: Alicja
authors.initials: A
authors.lastname: Nowaczyk
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D018674:Adrenergic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018674:Adrenergic Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D010879:Piperazines; D011760:Pyrrolidinones; D018340:Receptors, Adrenergic, alpha-1