更新于：2024-11-01

S1PR1 x CB

更新于：2024-11-01

基本信息

关联

项与 S1PR1 x CB 相关的药物

TE-5126

靶点

CB x S1PR1 x S1PR2 x S1PR3 x S1PR4 x TfR1

作用机制

CB拮抗剂 [+5]

在研机构

免疫功坊股份有限公司

原研机构

免疫功坊股份有限公司

在研适应症

多发性硬化症

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

Oxfenmino Hydrochloride

盐酸奥芬米洛

靶点

CB x S1PR1

作用机制

CB拮抗剂 [+1]

在研机构-

原研机构

浙江中医药大学

在研适应症-

非在研适应症

多发性硬化症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 S1PR1 x CB 相关的临床结果

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100 项与 S1PR1 x CB 相关的转化医学

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0 项与 S1PR1 x CB 相关的专利（医药）

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项与 S1PR1 x CB 相关的文献（医药）

2024-11-01·Neurobiology of Disease

Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease

Article

作者: Martínez-Gardeazabal, Jonatan ; Moreno-Rodríguez, Marta ; Manuel, Iván ; Llorente-Ovejero, Alberto ; Fernández, Manuel ; Pereira-Castelo, Gorka ; Rodríguez-Puertas, Rafael ; Fernández-Vega, Iván

Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P₁), is coupled to G_i/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P₁ constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P₁ receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P₁ receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [³⁵S]GTPγS binding stimulated by the S1P₁ receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P₁ receptors. S1P₁ receptor-mediated activity, along with that of the cannabinoid CB₁ receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P₁ signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P₁ receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P₁ receptor activity and Braak stages, suggesting that S1P₁ receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P₁ receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P₁ receptor-mediated responses in the human brain.

2022-12-01·Molecular Pharmacology

Differential Enantiomer-Specific Signaling of Cannabidiol at CB₁Receptors

Article

作者: Nikas, Spyros P ; Mackie, Ken P ; Iliopoulos-Tsoutsouvas, Christos ; Jiang, Shan ; Wilson, Sierra ; Straiker, Alex ; Wager-Miller, Jim ; Bosquez-Berger, Taryn ; Makriyannis, Alexandros

The two main constituents of cannabis are Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ⁹-THC pharmacology has been studied extensively, CBD-long considered inactive-is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-all. However, our understanding of CBD pharmacology remains limited, although CBD inhibits cannabinoid CB₁ receptor signaling, likely as a negative allosteric modulator. Cannabis synthesizes (-)-CBD, but CBD can also exist as an enantiomer, (+)-CBD. We enantioselectively synthesized both CBD enantiomers using established conditions and describe here a new, practical, and reliable, NMR-based method for confirming the enantiomeric purity of two CBD enantiomers. We also investigated the pharmacology of (+)-CBD in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and in CHO-K1 cells. We report the inhibition constant for displacing CP55,940 at CB₁ by (+)-CBD, is 5-fold lower than (-)-CBD. We find that (+)-CBD is ∼10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endogenous cannabinoid-mediated retrograde synaptic plasticity. (+)-CBD also inhibits CB₁ suppression of cAMP accumulation but with less potency, indicating that the signaling profiles of the enantiomers differ in a pathway-specific manner. In addition, we report that (+)-CBD stereoselectively and potently activates the sphingosine-1 phosphate (S1P) receptors, S1P₁ and S1P₃ These results provide an attractive method for synthesizing and distinguishing enantiomers of CBD and related phytocannabinoids and provide further evidence that these enantiomers have their own unique and interesting signaling properties. SIGNIFICANCE STATEMENT: Cannabidiol (CBD) is the subject of considerable scientific and popular interest, but we know little of the enantiomers of CBD. We find that the enantiomer (+)-CBD is substantially more potent inhibitor of cannabinoid CB₁ receptors and that it activates sphingosine-1-phosphate receptors in an enantiomer-specific manner; we have additionally developed an improved method for the synthesis of enantiomers of CBD and related compounds.

2021-01-01·Pharmacological Research2区 · 医学

Deciphering the cellular mechanisms underlying fibrosis-associated diseases and therapeutic avenues

2区 · 医学

Review

作者: Guo, Yan ; Miao, Hua ; Wang, Yan-Ni ; Xiong, Qingping ; Li, Ping ; Zhao, Ying-Yong ; Zhang, Dan-Dan ; Wu, Xia-Qing

Fibrosis is the excessive deposition of extracellular matrix components, which results in disruption of tissue architecture and loss of organ function. Fibrosis leads to high morbidity and mortality worldwide, mainly due to the lack of effective therapeutic strategies against fibrosis. It is generally accepted that fibrosis occurs during an aberrant wound healing process and shares a common pathogenesis across different organs such as the heart, liver, kidney, and lung. A better understanding of the fibrosis-related cellular and molecular mechanisms will be helpful for development of targeted drug therapies. Extensive studies revealed that numerous mediators contributed to fibrogenesis, suggesting that targeting these mediators may be an effective therapeutic strategy for antifibrosis. In this review, we describe a number of mediators involved in tissue fibrosis, including aryl hydrocarbon receptor, Yes-associated protein, cannabinoid receptors, angiopoietin-like protein 2, high mobility group box 1, angiotensin-converting enzyme 2, sphingosine 1-phosphate receptor-1, SH2 domain-containing phosphatase-2, and long non-coding RNAs, with the goal that drugs targeting these important mediators might exhibit a beneficial effect on antifibrosis. In addition, these mediators show profibrotic effects on multiple tissues, suggesting that targeting these mediators will exert antifibrotic effects on different organs. Furthermore, we present a variety of compounds that exhibit therapeutic effects against fibrosis. This review suggests therapeutic avenues for targeting organ fibrosis and concurrently identifies challenges and opportunities for designing new therapeutic strategies against fibrosis.