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NV-5138 Sale

目录号 : GC63121

A sestrin modulator and mTORC1 activator

NV-5138 Chemical Structure

Cas No.:2095886-80-7

规格 价格 库存 购买数量
5 mg
¥2,250.00
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10 mg
¥3,600.00
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25 mg
¥7,650.00
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50 mg
¥12,150.00
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100 mg
¥17,550.00
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产品描述

NV-5138 is a sestrin modulator and mammalian target of rapamycin protein complex 1 (mTORC1) activator.1 It binds to sestrin 2 (Kd = 1.49 ?M) and induces dissociation of sestrin 2 from the multimeric mTORC1 inhibitory complex GATOR2 and mTORC1 activation when used at concentrations ranging from 30 to 100 ?M. NV-5138 (40, 80, or 160 mg/kg) reduces immobility time in the forced swim test and latency to feed in the novelty-suppressed feeding test, indicating antidepressant- and anxiolytic-like activity, respectively, in rats, effects that can be reversed by the mTORC1 inhibitor rapamycin .2 It also reverses behavioral and synaptic deficits in a rat model of chronic stress-induced depression.

1.Sengupta, S., Giaime, E., Narayan, S., et al.Discovery of NV-5138, the first selective Brain mTORC1 activatorSci. Rep.9(1)4107(2019) 2.Kato, T., Pothula, S., Liu, R.-J., et al.Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activationJ. Clin. Invest.129(6)2542-2554(2019)

Chemical Properties

Cas No. 2095886-80-7 SDF
分子式 C7H13F2NO2 分子量 181.18
溶解度 储存条件 Store at -20°C,unstable in solution, ready to use.
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溶解性数据

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1 mM 5.5194 mL 27.5969 mL 55.1937 mL
5 mM 1.1039 mL 5.5194 mL 11.0387 mL
10 mM 0.5519 mL 2.7597 mL 5.5194 mL
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Research Update

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status

CNS Drugs 2021 May;35(5):527-543.PMID:33904154DOI:10.1007/s40263-021-00816-x.

The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

NV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling

J Clin Invest 2019 May 20;129(6):2207-2209.PMID:31107245DOI:10.1172/JCI129702.

Growing evidence implicates altered mTORC1 signaling cascades in the pathophysiology of depression, suggesting that direct modulation of mTORC1 signaling may offer novel therapeutic potential. In this issue of the JCI, Kato and colleagues reported that administration of NV-5138, a recently developed synthetic leucine analog, has a rapid and sustained antidepressant action in rat models via activation of mTORC1 signaling. The investigators also found that the antidepressant effect of NV-5138 is mediated by upregulation of brain-derived neurotrophic factor (BDNF) signaling and that NV-5138 treatment produces rapid synaptic responses in the medial prefrontal cortex. These findings highlight the direct activation of mTORC1 signaling as a potential pharmacological intervention for the treatment of depression.

Discovery of NV-5138, the first selective Brain mTORC1 activator

Sci Rep 2019 Mar 11;9(1):4107.PMID:30858438DOI:10.1038/s41598-019-40693-5.

The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.

Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation

J Clin Invest 2019 Apr 16;129(6):2542-2554.PMID:30990795DOI:10.1172/JCI126859.

Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.