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更新于：2026-03-28

UCPH-101

更新于：2026-03-28

概要

概要

基本信息

药物类型

小分子化药

别名

UCPH-101

靶点

EAAT1

作用方式

阻滞剂

作用机制

EAAT1 blockers(solute carrier family 1 member 3 blockers)

治疗领域-

在研适应症-

非在研适应症-

原研机构

University of Copenhagen

在研机构

University of Copenhagen

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C27H22N2O3

InChIKeyYBMGNDPBARCLFT-UHFFFAOYSA-N

CAS号1118460-77-7

关联

100 项与 UCPH-101 相关的临床结果

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100 项与 UCPH-101 相关的转化医学

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100 项与 UCPH-101 相关的专利（医药）

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项与 UCPH-101 相关的文献（医药）

2025-12-01·IBRO Neuroscience Reports

Brain pericytes upregulate glutamate uptake by astrocytes in vitro through sodium-dependent transporter

Article

作者: Sakai, Kenta ; Yasunaga, Miho ; Iwao, Takuro ; Yamanaka, Gaku ; Takata, Fuyuko ; Dohgu, Shinya ; Kataoka, Yasufumi

Astrocytes maintain glutamate homeostasis in the central nervous system (CNS) via glutamate uptake through Na⁺-dependent excitatory amino acid transporters (EAAT1 and EAAT2), and this process is regulated by several CNS cell types. However, it is unclear whether brain pericytes regulate glutamate uptake by astrocytes. Therefore, in this study, we aimed to investigate the effects of pericytes on the uptake of extracellular glutamate by astrocytes using an in vitro co-culture model of human brain-derived pericytes and astrocytes (pericyte co-cultures). The [³H]-L-glutamate ([³H]-L-Glu) uptake rate of astrocytes in pericyte co-cultures was significantly higher than that in astrocyte monocultures. Under Na⁺-free conditions, [³H]-L-Glu uptake by astrocytes was significantly inhibited in astrocyte monocultures and pericyte co-cultures. The inhibitory effect of Na⁺ depletion on glutamate uptake by astrocytes was more pronounced in pericyte co-cultures than in astrocyte monocultures. These findings suggest that glutamate uptake by astrocytes through the Na⁺-dependent transporter EAATs is upregulated by pericytes. Treatment with dihydrokainic acid, a selective inhibitor of EAAT2, significantly inhibited [³H]-L-Glu uptake by astrocytes in pericyte co-cultures but not in astrocyte monocultures. Treatment with UCPH-101, a selective inhibitor of EAAT1, significantly inhibited [³H]-L-Glu uptake by astrocytes in both monocultures and pericyte co-cultures. The UCPH-101-induced reduction in [³H]-L-Glu uptake by astrocytes in pericyte co-cultures was similar to that observed in astrocyte monocultures. These results suggest that pericytes upregulate glutamate uptake via EAAT2 in astrocytes. Furthermore, [³H]-L-Glu uptake in astrocytes significantly increased when astrocytes were treated with pericyte-conditioned medium. This finding suggests that pericyte-derived soluble factors contribute to the upregulation of astrocytic glutamate uptake. To our knowledge, this is the first study to report that pericyte-released mediators upregulate the EAAT2-dependent uptake of extracellular glutamate in astrocytes.

2024-03-01·Brain, behavior, and immunity

Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice

Article

作者: Wang, Peng ; Xu, Xiaoxia ; Qiu, Gaolin ; Liu, Xuesheng ; Zhang, Chi ; Weng, Juntao ; Lu, Yao ; Zhang, Qunlin ; Mei, Bin ; Yang, Yueyue

BACKGROUND:

Glutamate metabolism disorder is an important mechanism of sepsis-associated encephalopathy (SAE). Astrocytes regulate glutamate metabolism. In septic mice, α2A adrenoceptor (α2A-AR) activation in the central nervous system provides neuroprotection. α2A-ARs are expressed abundantly in hippocampal astrocytes. This study was performed to determine whether hippocampal astrocytic α2A-AR activation confers neuroprotection against SAE and whether this protective effect is astrocyte specific and achieved by the modulation of glutamate metabolism.

METHODS:

Male C57BL/6 mice with and without α2A-AR knockdown were subjected to cecal ligation and puncture (CLP). They were treated with intrahippocampal guanfacine (an α2A-AR agonist) or intraperitoneal dexmedetomidine in the presence or absence of dihydrokainic acid [DHK; a glutamate transporter 1 (GLT-1) antagonist] and/or UCPH-101 [a glutamate/aspartate transporter (GLAST) antagonist]. Hippocampal tissue was collected for the measurement of astrocyte reactivity, GLT-1 and GLAST expression, and glutamate receptor subunit 2B (GluN2B) phosphorylation. In vivo real-time extracellular glutamate concentrations in the hippocampus were measured by ultra-performance liquid chromatography tandem mass spectrometry combined with microdialysis, and in vivo real-time hippocampal glutamatergic neuron excitability was assessed by calcium imaging. The mice were subjected to the Barnes maze and fear conditioning tests to assess their learning and memory. Golgi staining was performed to assess changes in the hippocampal synaptic structure. In vitro, primary astrocytes with and without α2A-AR knockdown were stimulated with lipopolysaccharide (LPS) and treated with guanfacine or dexmedetomidine in the presence or absence of 8-bromo- cyclic adenosine monophosphate (8-Br-cAMP, a cAMP analog). LPS-treated primary and BV2 microglia were also treated with guanfacine or dexmedetomidine. Astrocyte reactivity, PKA catalytic subunit, GLT-1 an GLAST expression were determined in primary astrocytes. Interleukin-1β, interleukin-6 and tumor necrosis factor-alpha in the medium of microglia culture were measured.

RESULTS:

CLP induced synaptic injury, impaired neurocognitive function, increased astrocyte reactivity and reduced GLT-1 and GLAST expression in the hippocampus of mice. The extracellular glutamate concentration, phosphorylation of GluN2B at Tyr-1472 and glutamatergic neuron excitability in the hippocampus were increased in the hippocampus of septic mice. Intraperitoneal dexmedetomidine or intrahippocampal guanfacine administration attenuated these effects. Hippocampal astrocytes expressed abundant α2A-ARs; expression was also detected in neurons but not microglia. Specific knockdown of α2A-ARs in hippocampal astrocytes and simultaneous intrahippocampal DHK and UCPH-101 administration blocked the neuroprotective effects of dexmedetomidine and guanfacine. Intrahippocampal administration of DHK or UCPH-101 alone had no such effect. In vitro, guanfacine or dexmedetomidine inhibited astrocyte reactivity, reduced PKA catalytic subunit expression, and increased GLT-1 and GLAST expression in primary astrocytes but not in primary astrocytes that received α2A-AR knockdown or were treated with 8-Br-cAMP. Guanfacine or dexmedetomidine inhibited microglial reactivity in BV2 but not primary microglia.

CONCLUSIONS:

Our results suggest that neurocognitive protection against SAE after hippocampal α2A-AR activation is astrocyte specific. This protection may involve the inhibition of astrocyte reactivity and alleviation of glutamate neurotoxicity, thereby reducing synaptic injury. The cAMP/protein kinase A (PKA) signaling pathway is a potential cellular mechanism by which activating α2A-AR modulates astrocytic function.

2021-12-01·BMC Pharmacology & Toxicology

Computational determination of toxicity risks associated with a selection of approved drugs having demonstrated activity against COVID-19

Article

作者: Delgado, Williams Ernesto Miranda ; Tuszynski, Jack A ; Houghton, Michael ; Wacker, Soren ; Noskov, Sergey ; Tyrrell, D Lorne J ; Aminpour, Maral

Abstract:

Background:

The emergence and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in thelate 2019 has caused a devastating global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19). Although vaccines have been and are being developed, they are not accessible to everyone and not everyone can receive these vaccines. Also, it typically takes more than 10 years until a new therapeutic agent is approved for usage. Therefore, repurposing of known drugs can lend itself well as a key approach for significantly expediting the development of new therapies for COVID-19.

Methods:

We have incorporated machine learning-based computational tools and in silico models into the drug discovery process to predict Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of 90 potential drugs for COVID-19 treatment identified from two independent studies mainly with the purpose of mitigating late-phase failures because of inferior pharmacokinetics and toxicity.

Results:

Here, we summarize the cardiotoxicity and general toxicity profiles of 90 potential drugs for COVID-19 treatment and outline the risks of repurposing and propose a stratification of patients accordingly. We shortlist a total of five compounds based on their non-toxic properties.

Conclusion:

In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for treating COVID-19.

100 项与 UCPH-101 相关的药物交易

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