更新于：2024-11-21

Xamoterol Fumarate

富马酸扎莫特罗

更新于：2024-11-21

概要

概要

基本信息

药物类型

小分子化药

别名

Xamoterol、Xamoterol fumarate (USAN)

+ [4]

靶点

β1-adrenergic receptor

作用机制

β1-adrenergic receptor激动剂(β1-肾上腺素能受体激动剂)

治疗领域

神经系统疾病心血管疾病

在研适应症

心脏衰竭直立性低血压

非在研适应症-

原研机构-

在研机构-

非在研机构-

最高研发阶段批准上市

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C16H25N3O5

InChIKeyDXPOSRCHIDYWHW-UHFFFAOYSA-N

CAS号81801-12-9

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关联

100 项与富马酸扎莫特罗相关的临床结果

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100 项与富马酸扎莫特罗相关的转化医学

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100 项与富马酸扎莫特罗相关的专利（医药）

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288

项与富马酸扎莫特罗相关的文献（医药）

2023-02-01·Molecular Pharmacology

The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Humanβ1-Adrenoceptor

Article

作者: Kolb, Peter ; Monteleone, Stefania ; Proudman, Richard G W ; Lim, Victor Jun Yu ; Baker, Jillian G

Known off-target interactions frequently cause predictable drug side-effects (e.g., β1-antagonists used for heart disease, risk β2-mediated bronchospasm). Computer-aided drug design would improve if the structural basis of existing drug selectivity was understood. A mutagenesis approach determined the ligand-amino acid interactions required for β1-selective affinity of xamoterol and nebivolol, followed by computer-based modeling to provide possible structural explanations. ³H-CGP12177 whole cell binding was conducted in Chinese hamster ovary cells stably expressing human β1, β2, and chimeric β1/β2-adrenoceptors (ARs). Single point mutations were investigated in transiently transfected cells. Modeling studies involved docking ligands into three-dimensional receptor structures and performing molecular dynamics simulations, comparing interaction frequencies between apo and holo structures of β1 and β2-ARs. From these observations, an ICI89406 derivative was investigated that gave further insights into selectivity. Stable cell line studies determined that transmembrane 2 was crucial for the β1-selective affinity of xamoterol and nebivolol. Single point mutations determined that the β1-AR isoleucine (I118) rather than the β2 histidine (H93) explained selectivity. Studies of other β1-ligands found I118 was important for ICI89406 selective affinity but not that for betaxolol, bisoprolol, or esmolol. Modeling studies suggested that the interaction energies and solvation of β1-I118 and β2-H93 are factors determining selectivity of xamoterol and ICI89406. ICI89406 without its phenyl group loses its high β1-AR affinity, resulting in the same affinity as for the β2-AR. The human β1-AR residue I118 is crucial for the β1-selective affinity of xamoterol, nebivolol, and ICI89406 but not all β1-selective compounds. SIGNIFICANCE STATEMENT: Some ligands have selective binding affinity for the human β1 versus the β2-adrenoceptor; however, the molecular/structural reason for this is not known. The transmembrane 2 residue isoleucine I118 is responsible for the selective β1-binding of xamoterol, nebivolol, and ICI89406 but does not explain the selective β1-binding of betaxolol, bisoprolol, or esmolol. Understanding the structural basis of selectivity is important to improve computer-aided ligand design, and targeting I118 in β1-adrenoceptors is likely to increase β1-selectivity of drugs.

2022-10-01·Molecular Biology Reports

Mechanisms of β-adrenergic receptors agonists in mediating pro and anti-apoptotic pathways in hyperglycemic Müller cells

Article

作者: Ali, Abid ; Latif, Zahina ; Saeed, Laiba ; Shah, Humaira ; Imran, Muhammad ; Emran, Talha Bin ; Muhammad, Nawshad ; Safi, Sher Zaman ; Ismail, Ikram Shah Bin ; Subramaniyan, Vetriselvan

BACKGROUNDThe current study aimed to investigate the stimulatory effect of beta-adrenergic receptors (β-ARs) on brain derived neurotropic factor (BDNF) and cAMP response element binding protein (CREB).METHODSHuman Müller cells were cultured in low and high glucose conditions. Cells were treated with xamoterol (selective agonist for β1-AR), salmeterol (selective agonist for β2-AR), isoproterenol (β-ARs agonist) and propranolol (β-ARs antagonist), at 20 µM concentration for 24 h. Western Blotting assay was performed for the gene expression analysis. DNA damage was evaluated by TUNEL assay. DCFH-DA assay was used to check the level of reactive oxygen species (ROS). Cytochrome C release was measured by ELISA.RESULTSXamoterol, salmeterol and isoproterenol showed no effect on Caspase-8 but it reduced the apoptosis and increased the expression of BDNF in Müller cells. A significant change in the expression of caspase-3 was observed in cells treated with xamoterol and salmeterol as compared to isoproterenol. Xamoterol, salmeterol and isoproterenol significantly decreased the reactive oxygen species (ROS) when treated for 24 hours. Glucose-induced cytochrome c release was disrupted in Müller cells.CONCLUSIONβ-ARs, stimulated by agonist play a protective role in hyperglycemic Müller cells, with the suppression of glucose-induced caspase-3 and cytochrome c release. B-Ars may directly mediate the gene expression of BDNF.

2021-09-01·Archives of Oral Biology4区 · 医学

Release of secretory immunoglobulin A by submandibular gland via β adrenergic receptor stimulation

4区 · 医学

Article

作者: Wakao, Yuki ; Okabayashi, Ken ; Narita, Takanori

OBJECTIVESecretory immunoglobulin A (sIgA) is important for mucosal immunity due to the inhibition of pathogen infection. The submandibular gland is known to secrete more sIgA than the parotid and sublingual glands. In this study, we focused on the relationship between the secretion of accumulated intracellular sIgA and β-adrenergic receptor stimulation, and clarified the autonomic regulatory mechanism of sIgA secretion in submandibular gland cells using dispersed gland cells.DESIGNSprague-Dawley rats (male, 6 weeks old, 200-250 g) were euthanized and their submandibular glands were removed. Dispersed submandibular gland cells placed in Krebs-Ringer-Bicarbonate solution were stimulated by autonomic nerve agonists. The concentration of secreted sIgA was measured using a rat IgA ELISA kit. The results were analysed using ANOVA and Tukey's test.RESULTSCells stimulated with the non-selective β-adrenoreceptor agonist, isoprenaline, secreted significantly more sIgA compared with the unstimulated control. The β2-adrenoreceptor agonist, fenoterol, caused significantly more sIgA secretion than the control, and more sIgA secretion than the β1-adrenoreceptor agonist, xamoterol. sIgA secretion by isoprenaline stimulation was dose dependent. Inhibition of the β receptor by propranolol completely blocked sIgA secretion following isoprenaline stimulation.CONCLUSIONStimulation of β receptors could result in more secretion of intracellularly accumulated sIgA compared with stimulation of other autonomic receptors in the autonomic modulation of mucosal immunity.

100 项与富马酸扎莫特罗相关的药物交易

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