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-HT 7 receptor antagonists has been developed through structure-based design on the previously identified compound PZ-766. This resulted in highly potent antagonist 10 IJ3-fluoro-N-IJ1-{2-ij(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-HT 7 receptor antagonist properties and warrant further studies to explore their therapeutic potential for the treatment of CNS disorders.

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

“…In an attempt to further increase the uroselective profile, a limited series of compounds integrating silodosin-derived chemical scaffold was designed ( Figure 2 ). Selection of the central amine core (4-aminomethyl-piperidine and 3-amino-pyrrolidine), as well as a kind of substituent at the arylsulfonamide moiety, was based on our previously reported data presenting their preference for α 1A -AR over 5-HT 1A , and 5-HT 7 R [ 20 , 21 , 22 ].…”

Efficient and Sustainable Synthesis of a Potent and Selective 5-HT7 Receptor Antagonist Using a Mechanochemical Approach

“…After identifying the optimal reaction conditions for alkylation on a small scale, the influence of different substituent at the phenol was subsequently determined using a 35 mL PTFE jar. The choice of substituent (e.g., 2isopropyl and 2-iodo) was based on the biological data for this group of derivatives, wherein it was confirmed that only compounds bearing a sterically hindered substituent in 2-position preferentially bind to 5-HT 7 R. 23,24 a Reaction conditions: phenol (1 eq), epichlorohydrin (1.2 eq), vbm 30 Hz, ᴓball = 1.5 cm, time = 120-140 min, 35 mL PTFE jar; total mass of reagents: 330 mg. b 50 μL, η = 0.15 µL•mg -1 . c Conversions were determined by UPLC/MS analysis.…”

“…20,21 We have recently developed a novel class of potent and selective 5-HT 7 receptor (5-HT 7 R) antagonist, namely arylsulfonamide derivative of (aryloxy)alkyl alicyclic amine, and identified several lead structures that exhibit significant in vivo antidepressant and pro-cognitive properties in rodents (Figure 1). [22][23][24][25][26] Figure 1. Chemical structure of potent and selective 5-HT 7 R antagonist PZ-1361 belonging to the class of arylsulfonamides of (aryloxy)alkyl alicyclic amines.…”

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

“…However, the introduction of ─OH group at R 1 or ─CH 3 group at R 2 decreased the affinity at 5-HT 7 R when ─CH(CH 3 ) 2 substituent at o-position of ring B. As for the alkylene spacer between aryloxy and piperidine moiety, elongation from 2 to 3 slightly decreased the binding affinity at 5-HT 7 R yet maintained high selectivity over 5-HT 1A R. Moreover, alicyclic amine scaffold with one nitrogen was tolerable, displaying comparable affinities at 5-HT 7 R but different selectivity's over 5-HT 1A R. [112,117,118]…”