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MAP4343 Sale

目录号 : GC61400

MAP4343是Pregnenolone的3-甲基醚衍生物。MAP4343在体外与微管相关蛋白2(MAP2)结合,刺激微管蛋白的聚合,增强神经突的延伸并保护神经元免受神经毒性剂的侵害。

MAP4343 Chemical Structure

Cas No.:511-26-2

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10mM (in 1mL DMSO)
¥990.00
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5 mg
¥900.00
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10 mg
¥1,530.00
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25 mg
¥3,150.00
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50 mg
¥5,130.00
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100 mg
¥8,100.00
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产品描述

MAP4343 is the 3-methylether derivative of Pregnenolone. MAP4343 binds in vitro to microtubule-associated protein 2 (MAP2), stimulates the polymerization of tubulin, enhances the extension of neurites and protects neurons against neurotoxic agents[1][2].

MAP4343 (40 μM; 15 or 30 min) stimulates microtubule polymerization in vitro[1].MAP4343 (30 μM; 2-8 d) stimulates nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells[1].MAP4343 (20 μM; 1 h) protects against microtubule depolymerization induced by Nocodazole in PC12 cells[1]

MAP4343 (12 mg/kg; daily s.c. for 28 d) improves the recovery of locomotor function after spinal cord injury (SCI) in rats[2].MAP4343 (4 mg/kg; daily s.c. for 6 d) increases MAP2 levels in spinal cord after SCI in rats[2].MAP4343 (4 mg/kg; daily s.c. for 6 d) increases the size of lumbar spinal motoneurons' dendrite arbours after SCI in rats[2]. Animal Model: Adult Sprague-Dawley male rats with spinal cord injury[2]

[1]. Fontaine-Lenoir V, et, al. Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor. Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4711-6. [2]. Duchossoy Y, et, al. Treatment of experimental spinal cord injury with 3β-methoxy-pregnenolone. Brain Res. 2011 Jul 27;1403:57-66.

Chemical Properties

Cas No. 511-26-2 SDF
Canonical SMILES C[C@@]1([C@H]2C(C)=O)[C@](CC2)([H])[C@@](CC=C(C3)[C@@]4(CC[C@@H]3OC)C)([H])[C@]4([H])CC1
分子式 C22H34O2 分子量 330.5
溶解度 DMSO: 25 mg/mL (75.64 mM) 储存条件 Store at -20°C
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1 mM 3.0257 mL 15.1286 mL 30.2572 mL
5 mM 0.6051 mL 3.0257 mL 6.0514 mL
10 mM 0.3026 mL 1.5129 mL 3.0257 mL
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Research Update

Chronic MAP4343 reverses escalated alcohol drinking in a mouse model of alcohol use disorder

Neuropsychopharmacology 2023 Apr;48(5):821-830.PMID:36670228DOI:10.1038/s41386-023-01529-z.

Alcohol use disorders can be driven by negative reinforcement. Alterations of the microtubule cytoskeleton have been associated with mood regulation in the context of depression. Notably, MAP4343, a pregnenolone derivative known to promote tubulin assembly, has antidepressant properties. In the present study, we tested the hypothesis that MAP4343 may reduce excessive alcohol drinking in a mouse model of alcohol dependence by normalizing affect during withdrawal. Adult male C57BL/6J mice were given limited access to voluntary alcohol drinking and ethanol intake escalation was induced by chronic intermittent ethanol (CIE) vapor inhalation. Chronic, but not acute, administration of MAP4343 reduced ethanol intake and this effect was more pronounced in CIE-exposed mice. There was a complex interaction between the effects of MAP4343 and alcohol on affective behaviors. In the elevated plus maze, chronic MAP4343 tended to increase open-arm exploration in alcohol-naive mice but reduced it in alcohol-withdrawn mice. In the tail suspension test, chronic MAP4343 reduced immobility selectively in Air-exposed alcohol-drinking mice. Finally, chronic MAP4343 countered the plasma corticosterone reduction induced by CIE. Parallel analysis of tubulin post-translational modifications revealed lower α-tubulin acetylation in the medial prefrontal cortex of CIE-withdrawn mice. Altogether, these data support the relevance of microtubules as a therapeutic target for the treatment of AUD.

3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders

Proc Natl Acad Sci U S A 2012 Jan 31;109(5):1713-8.PMID:22307636DOI:10.1073/pnas.1121485109.

Emerging evidence suggests that the pathogenesis of depressive disorders (DDs) is associated with neuronal abnormalities in brain microtubule function, including changes in α-tubulin isoforms. Currently available antidepressant drugs may act by rescuing these alterations, but only after long-term treatment explaining their delayed therapeutic efficacy. The microtubule associated protein type-2 (MAP-2) modulates neuronal microtubule dynamics. Our hypothesis is that MAP-2 represents an innovative target for the treatment of DDs. The synthetic pregnenolone-derivative MAP4343 (3β-methoxy-pregnenolone) binds MAP-2 in vitro and increases its ability to stimulate tubulin assembly. Here, we show that MAP4343 has antidepressant efficacy in rats and advantages compared with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. A single injection of MAP4343 changes the expression of α-tubulin isoforms indicative of increased microtubule dynamics in the hippocampus of naïve Sprague-Dawley rats, whereas fluoxetine had no effects. MAP4343 has positive efficacy in the rat forced swimming test (FST), the most used assay to screen potential antidepressant drugs by decreasing immobility behavior. In the rat isolation-rearing model of depression, administration of MAP4343 showed more rapid and more persistent efficacy compared with fluoxetine in recovering "depressive-like" behaviors. These effects were accompanied by modifications of α-tubulin isoforms in the hippocampus, amygdala, and prefrontal cortex. Our findings suggest the potential therapeutic use of MAP4343 for the treatment of DDs, based on a unique mechanism of action.

[New therapeutic avenues for neurosteroids in psychiatric diseases]

Biol Aujourdhui 2019;213(3-4):131-140.PMID:31829933DOI:10.1051/jbio/2019023.

Discovered in the eighties by Pr Baulieu and colleagues, neurosteroids are a class of neuroactive brain-born steroids, which comprises the steroid hormones, their biosynthesis precursors and their metabolites. They can act through genomic as well as non-genomic pathways. Genomic pathways, only triggered by the neurosteroid hormones, are, in the brain, the same as those largely described in the periphery: the binding of these steroid hormones to nuclear receptors leads to transcription regulations. On the other hand, their precursors and metabolites, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), their respective sulfate esters, pregnenolone sulfate (PREG-S) and DHEA sulfate (DHEA-S) and allopregnanolone (ALLOP), are defined as neurosteroids, but no corresponding nuclear receptors have been identified so far. In fact, they trigger non-genomic pathways which consist in (i) inhibitory ionotropic receptors, (ii) excitatory ionotropic receptors and (iii) the microtubular system. Hence, inhibitory neurosteroids, whose mostly studied representative is ALLOP, positively modulate, or directly activate, the ionotropic GABA-A receptors. In contrast, excitatory neurosteroids, represented by PREG-S, DHEA-S and DHEA, inhibit the GABA-A receptors, and activate, directly or indirectly, through the sigma-1 receptors, the NMDA glutamate receptors. Neurosteroids of the third group, the microtubular neurosteroids, are able to bind microtubule associated proteins, in particular MAP2, to promote microtubule assembly, neurite outgrowth and in fine structural neuroplasticity. So far, PREG, DHEA and progesterone are the three identified microtubular neurosteroids. The pharmacological properties of neurosteroids have led to specific investigations for assessing their therapeutic potentialities in psychiatric diseases, using validated animal models. In some cases, clinical trials were also performed. These studies showed that ALLOP, the main inhibitory neurosteroid, displayed clear-cut anxiolytic-like and antidepressant-like efficacy in animals. It has been subsequently developed as Brexanolone and tested with success in phase III of clinical trials for the treatment of post-partum depression. Although showing pro-cognitive properties in animals, the sulfated neurosteroids, PREG-S and DHEA-S, were, in contrast, never tested in clinical trials, probably due to their poor stability and proconvulsivant side effects. Their respective non-sulfated forms, PREG and DHEA, showed antidepressant and antipsychotic efficacies in clinical trials, but these drugs never reached the phase III of clinical development because their therapeutic uses would have led to an overproduction of active metabolites responsible for intolerable side effects. The alternative strategy which has been selected consists of the development of non-metabolizable synthetic derivatives of these natural steroids, which keep the same neuroactive properties as their parent molecules, but are devoid of any hormonal side effects. An example of such innovative drugs is MAP4343, a synthetic derivative of PREG, which exhibits potent antidepressant-like efficacy in validated animal models. It is currently tested in depressed patients.

Effects of the Synthetic Neurosteroid: 3β-Methoxypregnenolone (MAP4343) on Behavioral and Physiological Alterations Provoked by Chronic Psychosocial Stress in Tree Shrews

Int J Neuropsychopharmacol 2016 Apr 20;19(4):pyv119.PMID:26476437DOI:10.1093/ijnp/pyv119.

Background: Most currently available active antidepressant drugs are selective serotonin/noradrenaline reuptake inhibitors. However, as their clinical efficacy is not immediate, long-term administration is often accompanied by substantial side effects, and numerous patients remain non- or partial responders. We have recently found that the synthetic neurosteroid derivative 3β-methoxypregnenolone, which binds to the microtubule-associated protein-2, can provide a novel therapeutic approach in experimental model of depressive disorders in rats. To further validate the antidepressant-like efficacy of 3β-methoxypregnenolone, we investigated effects of a longer treatment (4-week oral administration; 50mg/kg/d) in a nonrodent species, the tree shrew, exposed to psychosocial stress that elicits close-to-human alterations observed in patients with depressive disorders. Methods: During the experimental period, physiological parameters were registered, including core body temperature and electroencephalogram, while animals were videotaped to analyze their avoidance behavior. Morning urine samples were collected for measurements of cortisol and noradrenaline levels. Results: We found that treatment with 3β-methoxypregnenolone abolished stress-triggered avoidance behavior and prevented hormone hypersecretion, hypothermia, and sleep disturbances, further suggesting its antidepressant-like efficacy. Comparative treatment with fluoxetine also prevented some of the physiological alterations, while the hypersecretion of cortisol and sleep disturbances were not or partially restored by fluoxetine, suggesting a better efficacy of 3β-methoxypregnenolone. Alpha-tubulin isoforms were measured in hippocampi: we found that 3β-methoxypregnenolone reversed the specific decrease in acetylation of α-tubulin induced by psychosocial stress, while it did not modify the psychosocial stress-elicited reduction of tyrosinated α-tubulin. Conclusions: Taken together, these data strongly suggest a potent antidepressant-like effect of 3β-methoxypregnenolone on translational parameters.

Steroids and Brain, a Rising Bio-Medical Domain: a Perspective

Front Endocrinol (Lausanne) 2018 Jun 15;9:316.PMID:29963010DOI:10.3389/fendo.2018.00316.

Some newly described steroid-related compounds, also found in the rest of the body, are formed and active in the central nervous system, particularly in the brain. Some are of pharmacological and physiopathological interest. We specifically report on two compounds, "MAP4343," a new neurosteroid very efficient antidepressant, and "FKBP52," a protein component of hetero-oligomeric steroid receptors that we found involved in cerebral function, including in Alzheimer's disease.