Arylsulfonamide derivatives of (aryloxy)ethylpiperidines as selective 5-HT7 receptor antagonists and their psychotropic properties

Abstract

A series of alkyl/arylsulfonamide derivatives of (aryloxy)ethylpiperidines as highly potent 5-HT₇ receptor antagonists has been developed through structure-based design on the previously identified compound PZ-766. This resulted in highly potent antagonist10 (3-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl)-benzenesulfonamide) which was more active in vivo than PZ-766 and SB-269970 in forced swim test in mice (MED = 2.5 mg kg⁻¹), and displayed comparable effects to SB-269970 in four-plate test in mice (MED = 1.25 mg kg⁻¹) and novel object recognition test in rats (MED = 1 mg kg⁻¹). The results highlight the antidepressant, anxiolytic and pro-cognitive potential of the arylsulfonamide derivatives of (aryloxy)ethylpiperidines with 5-HT₇ receptor antagonist properties and warrant further studies to explore their therapeutic potential for the treatment of CNS disorders.