title: Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity.
abstract: A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α1-adrenoceptor antagonists with uroselective profile. Biological evaluation for α1- and α2-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α1-adrenoceptor (Ki=34-348nM) and moderate selectivity over α2-receptor subtype. Compounds with highest affinity and selectivity for α1-adrenoceptor were evaluated in vitro for their intrinsic activity toward α1A- and α1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α1-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α1A-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α1A-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.
authors.affiliation: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rak
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Canale
authors.affiliation: Department of Organic Chemistry, Medical University of Silesia, 4 Jagiellonska Street, 41-200 Sosnowiec, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Marciniec
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Żmudzki
authors.affiliation: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kotańska
authors.affiliation: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Knutelska
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Stachowicz
authors.affiliation: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: marek.bednarski@uj.edu.pl.
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Nowiński
authors.affiliation: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Zajdel
authors.affiliation: Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides
keywords: Arylsulfonamide derivatives of pyrrolidines and piperidines; Benign prostatic hyperplasia; LCAP flexible biomimetic; Uroselective activity; α(1)-Adrenoceptors antagonists; α(1A/B) receptor selectivity