Aryl Biphenyl‐3‐ylmethylpiperazines as 5‐HT₇ Receptor Antagonists

Abstract

The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

Synthesis of N‐Alkyl‐Carbazole Derivatives as 5‐HT7R Antagonists

“…Both compounds docked to the ligand‐binding site of the 5‐HT 7 R homology model structure by using the CDOCKER docking module in Discovery Studio. We have already found that there is a large and extended hydrophobic binding pocket in 5‐HT 7 R and the antagonists fully occupy the hydrophobic binding site . Both of 21 and 24 were smoothly bound to the 5‐HT 7 R binding site sufficiently covering the hydrophobic pocket, and the docking poses of the two compounds were similar (Figure (a) and (b)).…”

“…From the molecular docking study, 2D schematic molecule–protein interactions were deduced and shown in Figure (c) and (d). Like previously reported molecular docking studies, the key interaction was an ionic interaction between the protonated amino group of each compound and Asp162 in the 5‐HT 7 R binding site . Besides, both 21 and 24 showed additional interactions such as ionic interactions with ASP142, π–sulfur interactions with Cys166, carbon hydrogen bond interactions with Cys231, π–π interactions with Phe343, and π–alkyl interactions with Val 163, Leu232, Ile233 and Arg367.…”

“…Previously, our research group has reported N ‐acyl‐carbazole compounds as well as biaryl derivatives as selective 5‐HT 7 R ligands . As a continuation of our previous study, N ‐alkyl‐carbazole derivatives were investigated to study structure–activity relationship (SAR) of the carbazole derivatives (Figure ).…”

Chromium-Catalyzed, Regioselective Cross-Coupling of C–O Bonds by Using Organic Bromides as Reactants

“…IR (neat): 3068, 2843, 1686, 1593, 1558, 1461, 1396, 1279, 1195, 1024, 899, 830 cm-1 . Spectroscopic data are in accordance with those described in the literature 7.…”

“…-Chloro-biphenyl-2-carbaldehyde (3d)The general procedure was applied to N-(2-methoxybenzylidene)-tert-butylamine (38 mg, 0.2 mmol), Mg (11 mg, 0.44 mmol), 4-bromochlorobenzene (77 mg, 0.4 mmol) and CrCl 2 (3 mg, 0.02 mmol) at room temperature for 12 h. The crude product was purified by column S9 chromatography on silica gel (EtOAc/PE = 1/100) to afford the title compound as a colorless solid (26 mg, 60% yield). Melting point: 52-54 °C; 1 H NMR (400 MHz, CDCl 3 ): δ = 9.97 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H),7.44 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 192.0, 144.6, 136.4, 134.6, 133.82, 133.77, 131.4, 130.8, 128.8, 128.3, 128.0. IR (neat): 3062, 2973, 2881, 1684, 1595, 1468, 1403, 1247, 1193, 1087, 1003, 841, 825 cm -1 .Spectroscopic data are in accordance with those described in the literature 3.…”