Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression

Kim, Young-Jae; Tae, Jinsung; Lee, Kang-Ho; Rhim, Hyewhon; Choo, Il Han; Cho, Heeyeong; Park, Woo Kyu; Keum, Gyochang; Choo, Hyunah

doi:10.1016/j.bmc.2014.07.026

Cited by 24 publications

(23 citation statements)

References 47 publications

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“…Taken together, although the 5-HT 1A and 5-HT 7 receptors differ in terms of intracellular signaling, the functional consequences of zinc ions at a concentration of 10 μM at both receptors should result in the same decreasing effect on cAMP production and on further neuronal excitability. This is consistent with the antidepressant properties revealed by either the agonists of the 5-HT 1A receptor and the antagonists of the 5-HT 7 receptor in various behavioral models [ 72 – 77 ]. Moreover, because the 5-HT 1A and 5-HT 7 receptors are co-expressed in various brain regions and their functional cross talk has been suggested in depressive disorders, possibly through heterodimerization [ 25 , 78 ], the fine-tuning of receptor-mediated signaling by zinc ions can be hypothesized.…”

Section: Discussionsupporting

confidence: 87%

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

et al. 2017

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The allosteric regulation of G protein-coupled receptors (GPCRs) is a well-known phenomenon, but there are only a few examples of allosteric modulation within the metabotropic serotonergic receptor family. Recently, we described zinc non-competitive interactions toward agonist binding at serotonin 5-HT1A receptors, in which biphasic effects, involving potentiation at sub-micromolar concentrations (10 μM) and inhibition at sub-millimolar concentrations (500 μM) of Zn2+ in radioligand binding assays, were consistent with both the agonist and antagonist-like effects of zinc ions observed in in vivo studies. Here, we showed new data demonstrating zinc allosteric inhibition of both agonist and antagonist binding at human recombinant 5-HT7 receptors stably expressed in HEK293 cells as observed by radioligand binding studies as well as zinc neutral antagonism displayed by the concentration of 10 μM in the functional LANCE assay. The allosteric nature of the effect of Zn on 5-HT7 receptors was confirmed (1) in saturation studies in which zinc inhibited the binding of potent orthosteric 5-HT7 receptor radioligands, the agonist [3H]5-CT, and the two antagonists [3H]SB-269970 and [3H]mesulergine, showing ceiling effect and differences in the magnitude of negative cooperativity (α = 0.15, 0.06, and 0.25, respectively); (2) in competition experiments in which 500 μM of zinc inhibited all radioligand displacements by non-labeled orthosteric ligands (5-CT, SB-269970, and clozapine), and the most significant reduction in affinity was observed for the 5-CT agonist (4.9–16.7-fold) compared with both antagonists (1.4–3.9-fold); and (3) in kinetic experiments in which 500 μM zinc increased the dissociation rate constants for [3H]5-CT and [3H]mesulergine but not for [3H]SB-269970. Additionally, in the functional LANCE test using the constitutively active HEK293 cell line expressing the 5-HT7 receptor, 10 μM zinc had features of neutral antagonism and increased the EC50 value of the 5-CT agonist by a factor of 3.2. Overall, these results showed that zinc can act as a negative allosteric inhibitor of 5-HT7 receptors. Given that the inhibiting effects of low concentrations of zinc in the functional assay represent the most likely direction of zinc activity under physiological conditions, among numerous zinc-regulated proteins, the 5-HT7 receptor can be considered a serotonergic target for zinc modulation in the CNS.

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Section: Discussionsupporting

confidence: 87%

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

et al. 2017

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“…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)).…”

Section: Resultssupporting

confidence: 59%

“…Next, we selected the most active compounds 7 , 13 , and 14 , and a moderately active compound 15 for further SARs study, and the effect of alkyl chain length on 5‐HT 7 R binding affinity was examined . Thus, the chain length was sequentially reduced from n = 4 to n = 1, and the 5‐HT 7 R binding affinities of the corresponding compounds ( 16 – 27 ) were evaluated (Table ).…”

Section: Resultsmentioning

confidence: 67%

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

Kim

Yeom

Lee

et al. 2018

Bulletin Korean Chem Soc

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We designed and synthesized a series of N-alkyl-carbazoles with different alkyl chains and amine moieties, and biological evaluation was performed to discover novel 5-HT 7 R antagonists. Among 27 synthesized compounds, 20, 21, 23, and 24 showed excellent binding affinities to 5-HT 7 R (K i = 65, 64, 55, and 31 nM, respectively), and good selectivity profiles over other serotonin receptors. In functional assays, those compounds showed weak antagonistic activities against 5-HT 7 R. In particular, the compound 24, 2-(4-(5-(9H-carbazol-9-yl)pentyl)piperazin-1-yl)phenol, could be considered as a potent and selective 5-HT 7 R ligand with weak antagonistic effect. From the molecular docking study, the aromatic hydroxyl group in 24 was shown to play an important role in binding to 5-HT 7 R through a hydrogen bonding interaction with Asp142 in the ligand binding pocket of 5-HT 7 R.

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“…When the length of the carbon linker was varied, it was found that a 4-carbon chain resulted in the highest affinity for the 5-HT 7 receptor. 42 The substitution of the biphenyl group was then examined. The chlorophenyl substitution lead to the greatest increase in affinity.…”

Section: Long Chain Arylpiperazinesmentioning

confidence: 99%

Pharmacophore Comparison and Development of Recently Discovered Long Chain Arylpiperazine and Sulfonamide Based 5-HT7 Ligands

Rague

Tidgewell

2018

MRMC

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The serotonin system exerts its effects on the CNS and many peripheral systems. Of the 14 serotonin receptors, the 5-HT7 receptor is the most recently discovered. The 5-HT7 receptor has been shown to be involved in stress reduction, depression, and nociceptive control. Despite the 20 years since the discovery of 5-HT7R, there are still few truly selective ligands. Two of the common scaffolds for 5-HT7R ligands are long chain arylpiperazines (LCAPs) and sulfonamide containing compounds. This review focuses on recently developed (2014–2016) 5-HT7R ligands, their selectivity for the receptor, and suggests possible new pharmacophore models for these ligands.

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Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression

Cited by 24 publications

References 47 publications

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

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

Pharmacophore Comparison and Development of Recently Discovered Long Chain Arylpiperazine and Sulfonamide Based 5-HT7 Ligands

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Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression

Cited by 24 publications

References 47 publications

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

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

Pharmacophore Comparison and Development of Recently Discovered Long Chain Arylpiperazine and Sulfonamide Based 5-HT7 Ligands

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