Arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines as selective and potent 5-HT7 receptor antagonists with psychotropic properties


Canale, Vittorio


arylsulfonamides ; biomimetics of LCAP ; 5-HT7 receptor antagonists ; depression


According to the World Health Organization (WHO), it has been estimated that by the year 2020, depression will be the second leading cause of severe disabilities and premature death. Despite the progress in pharmacotherapy, the currently available antidepressant drugs display quite limited efficacy. A growing body of preclinical and clinical data has supported the hypothesis that antagonism of the 5-HT7 receptor (5-HT7R) might provide advantages over the currently available antidepressants. Additionally, it was found that 5-HT7R antagonists may be considered potential targets for the treatment of other CNS disorders related to depression such as anxiety and cognitive impairments.As part of the efforts in developing 5-HT7R ligands, a concept of flexible biomimetics of long-chain arylpiperazines (LCAPs) was proposed. This approach allowed the development of potent and selective 5-HT7R antagonists, namely, arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines, and identifying the lead structure, PZ-766. The latter displayed antidepressant-like properties and pro-cognitive activity in animal models. These encouraging results became the premise for the design and synthesis of an 80-membered library of diverse arylsulfonamide/amide/urea derivatives of (aryloxy)ethyl alicyclic amines. The structural modifications comprised the diversification at the sulfonamide (alkyl/aryl or N-alkyl substituents), the introduction of different moieties in an ortho position at the aryloxy fragment (small, sterically hindered or hydrophilic substituents), the replacement of sulfonamide with amide and urea moieties, and the diversification of the central amine core (azetidine, 8-azabicyclo[3.2.1]octane and 2,5-diazabicyclo[2.2.1]heptane scaffolds). To further confirm the postulated hypothesis of LCAP’s biomimetics, a small series of arylsulfonamide derivatives of LCAP, as direct analogs of the arylsulfonamides of (aryloxy)ethyl piperidines, was also designed and synthesized.The study identified several potent 5-HT7R antagonists that are selective over other related monoaminergic receptors (5-HT1A, 5-HT2A, 5-HT6, dopamine D2, adrenergic α1 and β1, histamine H1, muscarinic M1 receptors) and serotonin transporter (SerT). Some of these compounds displayed improved metabolic stability in comparison to the lead compound. Finally, the most promising compounds 15 (3-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-piperidin-4-yl)-benzenesulfonamide), 79 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl] piperidin-4-yl}-benzenesulfonamide) and 93 (3-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzene-sulfonamide) showed significant antidepressant properties in the forced swim test (MED = 0.625–2.5 mg/kg, i.p.) and in the tail suspension test (MED = 2.5 mg/kg, i.p.), as well as anxiolytic properties in the four-plate test (MED = 0.625–1.25 mg/kg, i.p.) in rodents. Additionally, the tested compounds displayed distinct pro-cognitive properties in NOR tasks (MED = 1 mg/kg, i.p.) in rats. These findings warrant further studies to explore the therapeutic potential of these derivatives for the treatment of CNS disorders.

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2 - studia doktoranckie

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Jagiellonian University Medical College. Faculty of Pharmacy. Chair of Pharmaceutical Chemistry. Department of Medicinal Chemistry.


Paweł Zajdel



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tylko w bibliotece

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Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum



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