N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT₇ receptor selectivity versus multireceptor profile

详细信息    查看全文

• 作者：Vittorio Canale^a ; Rafał Kurczab^b ; Anna Partyka^c ; Grzegorz Satała^b ; Karolina Słoczyńska^d ; Tomasz Kos^e ; Magdalena Jastrzębska-Więsek^c ; Agata Siwek^f ; Elżbieta Pękala^d ; Andrzej J. Bojarski^b ; Anna Wesołowska^c ; Piotr Popik^e ; Paweł Zajdel^a ; ^{pawel.zajdel@uj.edu.pl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：N-Alkylated sulfonamides ; 5-HT7 receptor antagonist ; Multimodal 5-HT/dopamine ligands ; Depression ; Cognitive deficits
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：24
• 期：2
• 页码：130-139
• 全文大小：1214 K

文摘

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-HT_2A/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.