Towards new 5-HT7 antagonists among arylsulfonamide derivatives of (aryloxy)ethyl-alkyl amines: Multiobjective based design, synthesis, and antidepressant and anxiolytic properties

• Novel arylsulfonamide/amide/urea derivatives of alicyclic amines.
• Application of virtual combinatorial library-virtual screening protocol for compound selection.
• Solid-supported synthesis of 39-membered library.
• Identification of potent and selective 5-HT7 receptors antagonists.
• Antidepressant and anxiolytic properties of 5-HT7 receptors antagonists.

A series of 39 arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines, was designed with the support of the Virtual Combinatorial Library-Virtual Screening protocol, and synthesized using solid-phase methodologies. Representative compounds were biologically evaluated for their affinity for 5-HT7Rs and for their selectivity over related 5-HTRs (5-HT1ARs, 5-HT2ARs, 5-HT6Rs), dopamine D2Rs and adrenergic α1Rs. The study identified the derivatives 27 (3-fluoro-N-{1-[2-(2-cyclopentylphenoxy)ethyl]piperidin-4-yl}-benzenesulfonamide; PZ-1417) and 35 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-yl)-benzenesulfonamide; PZ-1150) as being potent 5-HT7R antagonists with antidepressant and anxiolytic properties in the forced swim test (0.625–5 mg/kg and 0.625 mg/kg, respectively), the tail suspension test (0.625 mg/kg and 0.625 mg/kg, respectively), and in four plate test (0.625 mg/kg and 1.25–2.5 mg/kg, respectively) in mice. It has to be stressed that new compounds displayed higher activity than that of SB-269970, a reference 5-HT7R antagonist. Finally, the study provided valuable insight into the development of potential therapeutic agents for the treatment of CNS disorders.

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