N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT7 receptor selectivity versus multireceptor profile |
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| Affiliation: | 1. Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;2. Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland;3. Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;4. Department of Pharmaceutical Biochemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;5. Department of Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland;6. Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland;1. Department of Pharmacy—Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany;2. Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland;1. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Kraków, Poland;2. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Universitaetsstr. 1, 40225 Duesseldorf, Germany;3. Institute of General and Ecological Chemistry, Technical University of Łódź, Żeromskiego 116 Str., 90-924 Łódź, Poland;1. Aptuit s.r.l, Via Fleming 4, 37135 Verona, Italy;2. Indivior Inc, The Fairfax Building, 10710 Midlothian Turnpike, Suite 430, Richmond, VA 23235, USA;1. Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia;2. Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States;3. Institute for Medical Research, University of Belgrade, Dr. Subotića 4, 11129 Belgrade, Serbia |
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| 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. |
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| Keywords: | Multimodal 5-HT/dopamine ligands Depression Cognitive deficits |
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