A Multicentric, Open-label, Prospective, Non-comparative, Phase IV Clinical Study to Evaluate the Safety, Tolerability and Efficacy of FDC of Cilnidipine 20 mg plus Telmisartan 40 mg Film-Coated Tablets in subjects with Essential Hypertension - NIL

开始日期2024-10-21

申办/合作机构

Ajanta Pharma Ltd.

CTRI/2024/08/072999 / RecruitingN/AIIT

Comparison of the Efficacy of 24 Hour BP Control of Azelnidipine, Amlodipine and Cilnidipine in Mild to Moderate Essential Hypertension – a Prospective Multi-centric Parallel Arm Real-world Study (AMCILAZ-EH Study) - AMCILAZ-EH Study

开始日期2024-09-04

申办/合作机构-

100 项与 Cav2.2 x Cav1.2 相关的临床结果

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100 项与 Cav2.2 x Cav1.2 相关的转化医学

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0 项与 Cav2.2 x Cav1.2 相关的专利（医药）

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项与 Cav2.2 x Cav1.2 相关的文献（医药）

2022-07-01·Molecular Psychiatry1区 · 医学

Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings

1区 · 医学

Review

作者: Xiao, Xiao ; Li, Ming ; Chen, Jun ; Fang, Yiru ; Hu, Zhonghua ; Li, Tao

Genome-wide association studies (GWAS) have reported substantial genomic loci significantly associated with clinical risk of bipolar disorder (BD), and studies combining techniques of genetics, neuroscience, neuroimaging, and pharmacology are believed to help tackle clinical problems (e.g., identifying novel therapeutic targets). However, translating findings of psychiatric genetics into biological mechanisms underlying BD pathogenesis remains less successful. Biological impacts of majority of BD GWAS risk loci are obscure, and the involvement of many GWAS risk genes in this illness is yet to be investigated. It is thus necessary to review the progress of applying BD GWAS risk genes in the research and intervention of the disorder. A comprehensive literature search found that a number of such risk genes had been investigated in cellular or animal models, even before they were highlighted in BD GWAS. Intriguingly, manipulation of many BD risk genes (e.g., ANK3, CACNA1C, CACNA1B, HOMER1, KCNB1, MCHR1, NCAN, SHANK2 etc.) resulted in altered murine behaviors largely restoring BD clinical manifestations, including mania-like symptoms such as hyperactivity, anxiolytic-like behavior, as well as antidepressant-like behavior, and these abnormalities could be attenuated by mood stabilizers. In addition to recapitulating phenotypic characteristics of BD, some GWAS risk genes further provided clues for the neurobiology of this illness, such as aberrant activation and functional connectivity of brain areas in the limbic system, and modulated dendritic spine morphogenesis as well as synaptic plasticity and transmission. Therefore, BD GWAS risk genes are undoubtedly pivotal resources for modeling this illness, and might be translational therapeutic targets in the future clinical management of BD. We discuss both promising prospects and cautions in utilizing the bulk of useful resources generated by GWAS studies. Systematic integrations of findings from genetic and neuroscience studies are called for to promote our understanding and intervention of BD.

2022-04-19·Function

ADAM17 Mediates Proteolytic Maturation of Voltage-Gated Calcium Channel Auxiliary α2δ Subunits, and Enables Calcium Current Enhancement

Article

作者: Ellaway, Joseph I J ; Dolphin, Annette C ; Chaggar, Kanchan ; Troeberg, Linda ; Page, Karen M ; Nagase, Hideaki ; Dahimene, Shehrazade ; Kadurin, Ivan

AbstractThe auxiliary α2δ subunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function of CaV1 and CaV2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The α2δ proteins are translated as preproteins encoding both α2 and δ, and post-translationally proteolyzed into α2 and δ subunits, which remain associated as a complex. In this study, we have identified ADAM17 as a key protease involved in proteolytic processing of pro-α2δ-1 and α2δ-3 subunits. We provide three lines of evidence: First, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Second, proteolytic cleavage of both α2δ-1 and α2δ-3 is markedly reduced in cell lines by knockout of ADAM17 but not ADAM10. Third, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature α2δ is essential for the enhancement of CaV function, and in agreement, knockout of ADAM17 inhibited the ability of α2δ-1 to enhance both CaV2.2 and CaV1.2 calcium currents. Finally, our data also indicate that the main site of proteolytic cleavage of α2δ-1 is the Golgi apparatus, although cleavage may also occur at the plasma membrane. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of α2δ-1 and α2δ-3, and thus a potential drug target in neuropathic pain.

2021-11-01·Peptides3区 · 医学

Purification and characterization of peptides Ap2, Ap3 and Ap5 (ω-toxins) from the venom of the Brazilian tarantula Acanthoscurria paulensis

3区 · 医学

Article

作者: Schwartz, Elisabeth Ferroni ; de Souza, Adolfo Carlos Barros ; Mourão, Caroline Barbosa Farias ; Tibery, Diogo Vieira ; do Nascimento, Jonathan Martins

Peptides isolated from spider venoms are of pharmacological interest due to their neurotoxic activity, acting on voltage-dependent ion channels present in different types of human body tissues. Three peptide toxins titled as Ap2, Ap3 and Ap5 were purified by RP-HPLC from Acanthoscurria paulensis venom. They were partially sequenced by MALDI In-source Decay method and their sequences were completed and confirmed by transcriptome analysis of the venom gland. The Ap2, Ap3 and Ap5 peptides have, respectively, 42, 41 and 46 amino acid residues, and experimental molecular masses of 4886.3, 4883.7 and 5454.7 Da, with the Ap2 peptide presenting an amidated C-terminus. Amongst the assayed channels - NaV1.1, NaV1.5, NaV1.7, CaV1.2, CaV2.1 and CaV2.2 - Ap2, Ap3 and Ap5 inhibited 20-30 % of CaV2.1 current at 1 μM concentration. Ap3 also inhibited sodium current in NaV1.1, Nav1.5 and Nav1.7 channels by 6.6 ± 1.91 % (p = 0.0276), 4.2 ± 1.09 % (p = 0.0185) and 16.05 ± 2.75 % (p = 0.0282), respectively. Considering that Ap2, Ap3 and Ap5 belong to the 'U'-unknown family of spider toxins, which has few descriptions of biological activity, the present work contributes to the knowledge of these peptides and demonstrates this potential as channel modulators.

项与 Cav2.2 x Cav1.2 相关的新闻（医药）

2023-11-17

·生物谷

颜宁最新Cell论文：揭示药物调控钙离子通道Cav1.2的结构基础

无论是自由形式，还是与眼镜蛇毒素calciseptine、氨氯地平，胺碘酮与索非布韦结合，Cav1.2通道都呈现出一致的失活构象。在解析多种药物调控Cav1.2的作用机制的过程中，该研究获得三个重要的颜宁教授联合武汉大学药学院高帅教授、北京大学宋晨研究员，在 Cell 期刊发表了题为：Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine 的研究论文。该研究揭示了自由状态、多种药物结合、多肽毒素结合的钙离子通道Cav1.2的高分辨结构。无论是自由形式，还是与眼镜蛇毒素calciseptine、氨氯地平，胺碘酮与索非布韦结合，Cav1.2通道都呈现出一致的失活构象。在解析多种药物调控Cav1.2的作用机制的过程中，该研究获得三个重要的非预期发现：第一，尽管Cav1.2 与Cav1.3同属于L型钙离子通道，在功能及序列上高度同源，但Cav1.2在部分结构特性上更接近于神经钙离子通道Cav2.2/Cav2.3。具体而言，Cav1.2，Cav2.2，Cav2.3的电压感受结构域II （VSDII）处于down构象；Cav1.1，Cav1.3的VSDII则处于up构象；第二，该研究解析了眼镜蛇毒素calciseptine致死的分子机制，颠覆了以往对动物毒素调控离子通道功能的认知。经典的动物毒素结合模式一般是通过结合在离子孔结构域阻碍离子运输，或者结合在电压感受结构域变构调控离子通道功能。在本工作中，Calciseptine结合在Cav1.2离子孔外周的肩膀区域，这种崭新的结合模式稳定了Cav1.2通道失活状态的构象，导致蛋白功能抑制。毒素及蛋白定点突变电生理研究进一步验证了该结合模式；第三，该研究在解析胃肠道解痉剂匹维溴铵调控机制时，发现了Cav1.2通道的全新失活构象。在该构象中，VSDII呈现up状态，离子孔扩大，选择性滤器（SF）构象改变。与此同时，重复单元III的S4-S5与S5两个α螺旋元件融合成单个螺旋，导致细胞内孔（Intracellular gate）变宽。除匹维溴铵外，氨氯地平等其他药物分子不能结合该构象。通过分子动力学模拟证实，这个孔道结构域变大的构象仍不能通透钙离子，通道蛋白处于失活状态。武汉大学药学院高帅教授、深圳医学科学院颜宁教授、北京大学宋晨研究员为该论文共同通讯作者。武汉大学药学院高帅教授、姚霞教授、清华大学陈姣凤博士为论文共同第一作者。武汉大学药学院为文章第一完成单位。清华大学化学系刘磊教授、圣约翰大学于勇教授为该工作提供了关键技术支持。这是高帅教授在Nature（2021）、Cell Research（2022）、Cell（2022）、Nature Communications（2022）杂志发表钙离子通道镇痛药物齐考诺肽、抗晕动症药物桂利嗪，丙肝神药索非布韦副反应作用机制后，在该领域的又一系统性、突破性进展，为钙离子通道蛋白新型靶向药物研发奠定了重要的理论基础。