更新于：2024-11-01

5-HT6 receptor x GABAA receptor

更新于：2024-11-01

基本信息

关联

项与 5-HT6 receptor x GABAA receptor 相关的药物

Lead molecule 16(Adamed)

靶点

5-HT6 receptor x GABAA receptor

作用机制

5-HT6 receptor拮抗剂 [+1]

在研机构

Adamed Pharma S.A.

原研机构

Adamed Pharma S.A.

在研适应症

抑郁症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 5-HT6 receptor x GABAA receptor 相关的临床结果

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100 项与 5-HT6 receptor x GABAA receptor 相关的转化医学

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0 项与 5-HT6 receptor x GABAA receptor 相关的专利（医药）

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项与 5-HT6 receptor x GABAA receptor 相关的文献（医药）

2023-04-04·ACS chemical neuroscience

Dual Molecules Targeting 5-HT₆ and GABA-A Receptors as a New Approach to Combat Depression Associated with Neuroinflammation.

Article

作者: Mika, Kamil ; Kolaczkowski, Marcin ; Siwek, Agata ; Pomierny, Bartosz ; Marcinkowska, Monika ; Kotańska, Magdalena ; Głuch-Lutwin, Monika ; Mordyl, Barbara ; Bucki, Adam ; Pytka, Karolina ; Szafrańska, Katarzyna ; Sapa, Michał ; Gawalska, Alicja ; Karcz, Tadeusz

While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT₆ receptor activity. The serotonin 5-HT₆ receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT₆ and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

2023-02-01·European Journal of Medicinal Chemistry

Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

Article

作者: Pytka, Karolina ; Mordyl, Barbara ; Partyka, Anna ; Kotańska, Magdalena ; Gawalska, Alicja ; Siwek, Agata ; Marcinkowska, Monika ; Mika, Kamil ; Walczak, Maria ; Kolaczkowski, Marcin ; Pomierny, Bartosz ; Jastrzębska-Więsek, Magdalena ; Żmudzki, Paweł ; Bucki, Adam ; Karcz, Tadeusz ; Fajkis-Zajaczkowska, Nikola ; Smolik, Magdalena

There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT₆ receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT₆ receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.

2022-12-02·Cell Cycle

Effects of Cyclosporine A and Adalimumab on the expression profiles histaminergic system-associated genes and microRNAs regulating these genes in HaCaT cells

Article

作者: Boroń, Kacper ; Wierzbik-Strońska, Magdalena ; Zawidlak-Węgrzyńska, Barbara ; Dąbala, Maciej ; Kasela, Tomasz ; Mistarz, Magdalena ; Oskar Grabarek, Beniamin ; Wieczorek, Weronika

Previous studies have not completely elucidated the role of the histaminergic system in the pathogenesis of psoriasis. This study aimed to evaluate the effects of adalimumab and cyclosporine A on the expression of histaminergic system-related genes and miRNAs regulating these genes in bacterial lipopolysaccharide A (LPS)-stimulated human keratinocyte (HaCaT) cells. HaCaT cells were treated with 1 µg/mL LPS for 8 h, followed by treatment with 8 µg/mL adalimumab or 100 ng/mL cyclosporine A for 2, 8, or 24 h. Untreated cells served as controls. The cells were subjected to ribonucleic acid (RNA) extraction and microarray, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay analyses. Statistical analysis was performed using the Statistica 13.0 PL (StatSoft, Cracow, Poland) and the Transcriptome Analysis Console programs (Affymetrix, Santa Clara, CA, USA) (p < 0.05). The differential expression of the following two miRNAs was not affected in LPS-stimulated cells upon treatment with cyclosporine A or adalimumab: hsa-miR-583 (downregulated expression), involved in the regulation of histamine receptor 1 - HRH1 (overexpression); has-miR-1275 (downregulated expression), involved in the regulation of histamine receptor 1 - HRH3 (overexpression) and Solute carrier family 22 member 3 - SLC23A2 (downregulated expression)). Adalimumab and cyclosporine A modulated the histaminergic system in HaCaT cells in vitro. However, further studies are needed to elucidate the underlying mechanisms.Abbreviations: (-) - downregulated in comparison to the control, (+) - overexpression in comparison to the control, ACTB - β-actine, ADA - Adenosine deaminase, ADCYAP1 - Adenylate Cyclase Activating Polypeptide 1, BMP - bone morphogenetic protein, bp - base pair, cAMP - adenosine 3' 5'-cyclic monophosphate, CBX7 - Chromobox protein homolog 7, cDNA - double-stranded complementary DNA, CSA - cyclosporine A DAG - diacylglycerol, DIAPH - Diaphanous related formin 1, DNMT - DNA methyltransferases, DRD2 - Dopamine receptor D2, EDN1 - Endothelin 1, EDNRA - Endothelin receptor type A, ELISA - Enzyme-linked immunosorbent assay, EZH2 - Enhancer of zeste homolog 2, FC - fold change, GABRB1 - Gamma-aminobutyric acid (GABA) A receptor, alpha 1, GABRB2 - Gamma-aminobutyric acid (GABA) A receptor, alpha 2, GABRB3 - Gamma-aminobutyric acid (GABA) A receptor, alpha 3, HaCaT - Human adult, low-calcium, high-temperature keratinocytes, HIS - Human Histamine, HLAs - human leukocyte antigens, HNMT - Histamine N-methyltransferase, HNMT - Histamine N-Methyltransferase, HRH1 - histamine receptor 1, HRH2 - histamine receptor 2, HRH3 - histamine receptor 3, HRH4 - histamine receptor 4, HTR6 - 5-Hydroxytryptamine Receptor 6, IGF1 - Insulin-like growth factor 1, IL10 -interleukin 10, IL12 -interleukin 12, IL6 - interleukin 6, IP3 - inositol 1,4,5-triphosphate, LPS - bacterial lipopolysaccharide A, LYN - LYN Proto-Oncogene, Src Family Tyrosine Kinase, MAPKs -mitogen-activated protein kinases, miRNA - micro RNA, MMP2 - matrix metalloproteinase-2, NHDF - Normal Human Dermal Fibroblasts, NHEK - Normal Human Epidermal Keratinocytes, OCT3 - organic cation transporter 3, PANTHER - Protein ANalysis THrough Evolutionary Relationships Classification, PBS - phosphate-buffered saline, PI3K-AKT - phosphatidylinositol 3-kinase-protein kinase B, PIP2 - phosphatidylinositol 4,5 bisphosphate, PMSF - phenylmethylsulfonyl fluoride, PSORS1- psoriasis susceptibility gene 1, qRT-PCR - quantitative Reverse Transcription Polymerase Chain Reaction, RNA - ribonucleic acid, RNAi - RNA interference, RTqPCR - Real-Time Quantitative Reverse Transcription Reaction, SLC223A2 - Solute carrier family 22 member 3, SNX -Sorting nexin, SOX9 - SRY-Box Transcription Factor 9, TGF-α - transforming growth factor α, TGF-β - transforming growth factor beta, TNF-α - tumor necrosis factor alpha, TP53 - tumor protein 5 z, VAMP2 - Vesicle associated membrane protein 2.