更新于：2024-11-01

Toloxatone

托洛沙酮

更新于：2024-11-01

概要

概要

基本信息

药物类型

小分子化药

别名

Toloxatone (INN)、Humoryl

+ [2]

靶点

MAO-A

作用机制

MAO-A抑制剂(单胺氧化酶A抑制剂)

治疗领域

其他疾病

在研适应症

抑郁症

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

法国 (1984-01-01),

抑郁症

最高研发阶段(中国)-

特殊审评-

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结构

分子式C11H13NO3

InChIKeyMXUNKHLAEDCYJL-UHFFFAOYSA-N

CAS号29218-27-7

关联

100 项与托洛沙酮相关的临床结果

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100 项与托洛沙酮相关的转化医学

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100 项与托洛沙酮相关的专利（医药）

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项与托洛沙酮相关的文献（医药）

2022-06-01·Bioorganic Chemistry2区 · 化学

Coumarin derivatives as inhibitors of d-amino acid oxidase and monoamine oxidase

2区 · 化学

Article

作者: Petzer, Anél ; Bester, Elizabeth ; Petzer, Jacobus P

d-Amino acid oxidase (DAAO) oxidises d-amino acids to ultimately produce the corresponding α-keto acids. The DAAO substrate, d-serine, is a co-agonist at NMDA receptors, while NMDA receptor hypo-function has been implicated in the pathophysiology of schizophrenia. Through the modulation of d-serine levels, the inhibition of DAAO represents a strategy to increase NMDA receptor function, and thus a potential treatment for schizophrenia. Literature reports that 3-hydroxycoumarin is a potent inhibitor of DAAO and represents an ideal lead for the development of novel DAAO inhibitors. Based on this, the present study investigated DAAO inhibition by a series of synthetic and commercially available coumarin derivatives. Due to structural similarity to coumarin, a synthetic series of 3,4-dihydroisoquinolin-1(2H)-one derivatives has also been included in this study. The results show that among 37 compound evaluated, four inhibit porcine kidney DAAO with IC₅₀ < 10 µM. The most potent inhibitors are 3,7-dihydroxycoumarin and 6,7-dihydroxycoumarin with an IC₅₀ values of 0.167 and 0.224 µM, respectively. These values are an improvement on that of the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC₅₀ = 1.88 µM). Coumarin compounds are also known to inhibit the monoamine oxidase (MAO) enzymes, which are well established targets for the treatment of depression and Parkinson's disease. As DAAO and MAO are flavoenzymes, off-target inhibition may occur. The series were thus evaluated as potential MAO inhibitors, and a number of high potency inhibitors were identified. Seven compounds inhibit the recombinant human MAOs with IC₅₀ < 0.1 µM, with the most potent MAO-A and MAO-B inhibitors exhibiting IC₅₀ values of 0.033 and 0.012 µM, respectively. This is significantly more potent than the reference inhibitors, curcumin, isatin and toloxatone. This study concludes that active DAAO and MAO inhibitors may serve as novel leads for the design of compounds that may find future application in the treatment of neuropsychiatric (e.g. schizophrenia, depression) and neurodegenerative disorders (e.g. Parkinson's disease).

2019-06-01·IBRO Reports

The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents

Review

作者: Fasipe, Olumuyiwa John

This study was designed with the rational aim of discussing the emerging antidepressant agents that are likely to bring positive landmark, tremendous improvement and significant impact to the management of patients with depression disorders. It also elaborates on the Agomelatine paradox vis-a-vis the other novel antidepressant agents. The emerging antidepressants are: selective monoamine oxidase inhibitors (MAOIs) such as bifemelane, pirlindole, toloxatone, selegiline, rasagiline and safinamide; serotonin-norepinephrine reuptake inhibitors (SNRIs) such as ansofaxine, nefopam and levomilnacipran; norepinephrine reuptake inhibitors (NRIs) such as Reboxetine, viloxazine, teniloxazine (also known as sulfoxazine or sufoxazine), and atomoxetine; Vilazodone (a serotonin 5-HT_1A autoreceptor partial agonist with serotonin reuptake inhibition [SPARI]); Vortioxetine (a serotonin receptors antagonist with serotonin reuptake inhibition [SARI]); atypical antipsychotics such as olanzapine, quetiapine, risperidone, lurasidone, aripiprazole and brexpiprazole; N-methyl-d-aspartate (NMDA)-glutamatergic neurotransmission system blockers such as ketamine, CP-101,606 (traxoprodil), GLYX-13 (rapastinel), NRX-1074 (Apimostinel) and Riluzole. While Agomelatine (a melatonergic MT ₁ and MT ₂ receptors agonist and a selective serotonergic 5-HT _2B and 5-HT _2C receptors antagonist [MASSA]) remains a paradoxical agent that doesn't fit into any of the currently available classes of antidepressant agents and its pharmacological properties also deemed it unfit and inappropriate to be classified into another separate novel class of antidepressants contrary to the reports published in previous reference literatures. Lastly, this review remarkably advocates for the incorporation of the atypical antipsychotics and NMDA-glutamatergic ionoceptor blockers as new member classes of the antidepressant agents because of their clinically significant roles in the management of depression disorders.

2019-03-01·Bioorganic Chemistry2区 · 化学

Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A

2区 · 化学

Article

作者: Oh, Sei-Ryang ; Ryu, Hyung Won ; Kim, Hoon ; Park, Mi Hyeon ; Lee, Jae Pil ; Kang, Myung-Gyun ; Park, Chul Min ; Park, Daeui ; Baek, Seung Cheol

Three flavanones and two flavones were isolated from the leaves of Prunus padus var. seoulensis by the activity-guided screening for new monoamine oxidase (MAO) inhibitors. Among the compounds isolated, rhamnocitrin (5) was found to potently and selectively inhibit human MAO-A (hMAO-A, IC₅₀ = 0.051 µM) and effectively inhibit hMAO-B (IC₅₀ = 2.97 µM). The IC₅₀ value of 5 for hMAO-A was the lowest amongst all natural flavonoids reported to date, and the potency was 20.2 times higher than that of toloxatone (1.03 µM), a marketed drug. In addition, 5 reversibly and competitively inhibited hMAO-A and hMAO-B with K_i values of 0.030 and 0.91 µM, respectively. Genkwanin (4) was also observed to strongly inhibit hMAO-A and hMAO-B (IC₅₀ = 0.14 and 0.35 µM, respectively), and competitively inhibit hMAO-A and hMAO-B (K_i = 0.097 and 0.12 µM, respectively). Molecular docking simulation reveals that the binding affinity of 5 with hMAO-A (-18.49 kcal/mol) is higher than that observed with hMAO-B (0.19 kcal/mol). Compound 5 interacts with hMAO-A at four possible residues (Asn181, Gln215, Thr336, and Tyr444), while hMAO-B forms a single hydrogen bond at Glu84. These findings suggest that compound 5 as well as 4 can be considered as novel potent and reversible hMAO-A and/or hMAO-B inhibitors or useful lead compounds for future development of hMAO inhibitors in neurological disorder therapies.

100 项与托洛沙酮相关的药物交易

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