Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 6, Pages 618-622Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00056
Keywords
Isoquinoline/quinoline sulfonamides; 5-HT6 receptor antagonist; Alzheimer's disease; cognitive decline; novel object recognition task; forced swim test; Vogel test
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Funding
- project Prokog [UDA-POIG.01.03.01-12-063/09-00]
- European Union from the European Fund of Regional Development (EFRD)
- Polish Ministry of Science and Higher Education (MNiSW) [NN405 671540]
- Institute of Pharmacology, Polish Academy of Sciences
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A series of N1-azinylsulfonyl-3-(1,2,3,6,tetrahyrdopyridin-4-yl)-1H-indole derivatives was designed to obtain highly potent 5-HT6 receptor ligands. The study allowed for the identification of 25 (4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline), a potent and selective 5-HT6 receptor antagonist. The selected compound, was evaluated in vivo in a novel object recognition (NOR) and forced swim (FST) tests in rats, demonstrating distinct pro-cognitive and antidepressant-like properties (MED = 1 mg/kg and 0.1 mg/kg, i.p., respectively). Compound SB-742457, used as comparator, reversed memory deficits in NOR task in similar doses, while in FST it was active in 10-30-fold higher dose (3 mg/kg). In contrast to SB-742457, which was active in Vogel test (MED = 3 mg/kg), compound 25 displayed no anxiolytic activity.
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