N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties

Paweł Zajdel; Krzysztof Marciniec; Grzegorz Satała; Vittorio Canale; Tomasz Kos; Anna Partyka; Magdalena Jastrzębska-Więsek; Anna Wesołowska; Agnieszka Basińska-Ziobroń; Jacek Wójcikowski; Władysława A Daniel; Andrzej J Bojarski; Piotr Popik

doi:10.1021/acsmedchemlett.6b00056

N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties

ACS Med Chem Lett. 2016 Apr 7;7(6):618-22. doi: 10.1021/acsmedchemlett.6b00056. eCollection 2016 Jun 9.

Affiliations

¹ Department of Medicinal Chemistry and Department of Clinical Pharmacy, Jagiellonian University Medical College , 9 Medyczna Street, 30-688 Krakow, Poland.
² Department of Organic Chemistry, Medical University of Silesia , 4 Jagiellońska Street, 41-200 Sosnowiec, Poland.
³ Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, and Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, 31-343 Krakow, Poland.
⁴ Faculty of Health Sciences, Jagiellonian University Medical College, Michalowskiego 20, 31-126 Krakow, Poland; Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, and Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.

Abstract

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.

Keywords: 5-HT6 receptor antagonist; Alzheimer’s disease; Isoquinoline/quinoline sulfonamides; Vogel test; cognitive decline; forced swim test; novel object recognition task.