title: N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT(7) receptor selectivity versus multireceptor profile.
abstract: The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl-N-{1-[2-(2-(t-butyl)phenoxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), a potent and selective 5-HT7 receptor antagonist and 33 (1-methyl-N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT2A/5-HT7/D2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED=1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N-alkylated arylsulfonamides for the treatment of CNS disorders.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Canale
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Kurczab
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Słoczyńska
authors.affiliation: Department of Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kos
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.affiliation: Department of Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland. Electronic address: pawel.zajdel@uj.edu.pl.
authors.forename: Paweł
authors.initials: P
authors.lastname: Zajdel
mesh_terms: D000478:Alkylation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013550:Swimming
chemical_list: D010880:Piperidines; D011985:Receptors, Serotonin; D013449:Sulfonamides; C104425:serotonin 7 receptor
keywords: 5-HT(7) receptor antagonist; Cognitive deficits; Depression; Multimodal 5-HT/dopamine ligands; N-Alkylated sulfonamides