title: The multiobjective based design, synthesis and evaluation of the arylsulfonamide/amide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines as a novel class of potent 5-HT₇ receptor antagonists.
abstract: An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds 24-95 were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT(7)R. Additionally, the targeted library members were tested for 5-HT(1A), 5-HT(6), and D(2) receptors. Selected compounds of particular interest were examined for their intrinsic activity at 5-HT(7)R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT(7)R ligand (K(i) = 0.3 nM) with strong antagonistic properties (K(b) = 1 nM) and a 1450-fold selectivity over 5-HT(1A)Rs.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. mfzajdel@cyf-kr.edu.pl
authors.forename: Paweł
authors.initials: P
authors.lastname: Zajdel
authors.forename: Rafał
authors.initials: R
authors.lastname: Kurczab
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Grychowska
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
mesh_terms: D000577:Amides / Q000737:chemistry*; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D008024:Ligands; D010880:Piperidines; D011759:Pyrrolidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor