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JMV 449 Sale

目录号 : GC17784

JMV 449 是一种有效的神经降压素受体激动剂。

JMV 449 Chemical Structure

Cas No.:139026-66-7

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1mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

Rodent BRIN-BD11 beta-cells

Preparation Method

Cells were incubated (20 min) with JMV 449 alone (1×10-4-1µM), or in combination with GIP (1×10-4-1µM) or GLP-1 (1×10-4-1µM), as well as combination of all three test peptides.

Reaction Conditions

1×10-4-1µM JMV-449

Applications

JMV 449 displayed significant (P

Animal experiment [2]:

Animal models

Male C57BL/6 mice, 10 month old

Preparation Method

Cumulative food intake was assessed in overnight fasted (18h) mice following i.p. injection of saline vehicle (0.9% w/v NaCl) or test peptide (JMV 449, (D-Ala2)GIP, and exendin-4), with food intake measured at 30min intervals for 180min.

Dosage form

25nmol/kg

Applications

JMV 449, (D-Ala2)GIP, and exendin-4, induced a significant (P2)GIP and JMV 449, together with 2.5nmol/kg exendin-4, there was a significant reduction (P2)GIP plus exendin-4 injection alone.

References:

[1]. Irwin N. Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control. Biochim Biophys Acta Gen Subj. 2021;1865(8):129917

产品描述

JMV 449 is a potent, long-lasting neurotensin receptor agonist[1,2]. JMV 499 inhibits the binding of 125I-neurotensin to newborn mouse brain homogenates (IC50=0.15nm), and contracts isolated guinea-pig ileum preparations(EC50=1.9nM)[3].

JMV 449 induced noticeable dose-dependent insulin releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV 449 augmented(P<0.05) the insulinotropic actions of both hormones, as well as enhancing (P<0.001) insulin secretory activity of both incretin peptides[4]. JMV 449 induced high affinity neurotensin receptor (NTR) gene activation in the human neuroblastoma cell line CHP212[5]. JMV 449 (1M) was found to increase tyrosine hydroxylase protein and mRNA abundance after short- and long-term treatments (5 or 72h) in CHP212 cell[6]

MV 449 (25nmol/kg) inhibited (P<0.05–P<0.001) food intake in overnight fasted lean mice, and enhanced (P<0.01) the appetite suppressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV 449 evoked glucose lowering actions, but more interestingly significantly augmented (P<0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics[4].JMV 449 induces hypothermia and is able to decrease the infarct size both 24h and 14 days after the onset of permanent focal ischaemia demonstrates its significant neuroprotective potential in mouse model of permanent focal ischaemia[7]

References:
[1]. Dubuc I, Costentin J, et al. JMV 449: a pseudopeptide analogue of neurotensin-(8-13) with highly potent and long-lasting hypothermic and analgesic effects in the mouse. Eur J Pharmacol. 1992;219(2):327-329.
[2]. Craig SL, Gault VA, et al. Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control. Biochim Biophys Acta Gen Subj. 2021;1865(8):129917.
[3]. Lugrin D, Vecchini F, et al. Reduced peptide bond pseudopeptide analogues of neurotensin: binding and biological activities, and in vitro metabolic stability. Eur J Pharmacol. 1991;205(2):191-198.
[4]. Irwin N. Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control. Biochim Biophys Acta Gen Subj. 2021;1865(8):129917.
[5]. Najimi M, Souazé F, et al. Activation of receptor gene transcription is required to maintain cell sensitization after agonist exposure. Study on neurotensin receptor. J Biol Chem. 1998;273(34):21634-21641.
[6]. Najimi M, Hermans E, et al. Transcriptional regulation of the tyrosine hydroxylase gene by neurotensin in human neuroblastoma CHP212 cells. Metab Brain Dis. 2001;16(3-4):165-174.
[7]. Torup L, Borsdal J, et al. Neuroprotective effect of the neurotensin analogue JMV-449 in a mouse model of permanent middle cerebral ischaemia. Neurosci Lett. 2003;351(3):173-176.

JMV 449 是一种强效、长效的神经降压素受体激动剂[1,2]。 JMV 499 抑制125I-神经降压素与新生小鼠脑匀浆的结合(IC50=0.15nm),并收缩离体豚鼠回肠制剂(EC 50=1.9nM)[3].

JMV 449 在 BRIN-BD11 β 细胞中诱导显着的剂量依赖性胰岛素释放作用。结合 GIP 或 GLP-1,JMV 449 增强 (P<0.05) 两种激素的促胰岛素作用,以及增强 (P<0.001) 两种肠促胰岛素肽的胰岛素分泌活性[4]。 JMV 449 在人神经母细胞瘤细胞系 CHP212[5] 中诱导高亲和力神经降压素受体 (NTR) 基因激活。 JMV 449 (1M) 被发现在 CHP212 细胞中短期和长期处理(5 或 72 小时)后增加酪氨酸羟化酶蛋白和 mRNA 丰度[6]

MV 449 (25nmol/kg) 抑制 (P<0.05-P<0.001) 过夜禁食瘦小鼠的食物摄入,并增强 (P<0.01) 酶稳定 GLP-1 模拟物的食欲抑制作用。当与葡萄糖共同注射时,JMV 449 引起降糖作用,但更有趣的是显着增强 (P<0.05) 已建立的长效 GIP 和 GLP-1 受体模拟物的降糖作用[4].JMV 449 诱导低温并能够在永久性局灶性缺血发作后 24 小时和 14 天减少梗塞面积,证明其在永久性局灶性缺血小鼠模型中具有显着的神经保护潜力[7]

Chemical Properties

Cas No. 139026-66-7 SDF
化学名 (R)-2-((2S,3R)-2-((S)-2-((R)-1-((R)-6-amino-2-(((R)-2,6-diaminohexyl)amino)hexanoyl)pyrrolidine-2-carboxamido)-3-(4-hydroxyphenyl)propanamido)-3-methylpentanamido)-4-methylpentanoic acid
Canonical SMILES O=C([C@@H](CCCCN)NC[C@@H](CCCCN)N)N1[C@@H](C(N[C@H](C(N[C@H](C(N[C@@H](C(O)=O)CC(C)C)=O)[C@H](C)CC)=O)CC(C=C2)=CC=C2O)=O)CCC1
分子式 C38H66N8O7 分子量 746.96
溶解度 Soluble to 0.80 mg/ml in Water 储存条件 Desiccate at -20°C
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Research Update

Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control

Biochim Biophys Acta Gen Subj2021 Aug;1865(8):129917.PMID: 33964357DOI: 10.1016/j.bbagen.2021.129917

Background: Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist.
Methods: The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice.
Results: JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05-P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449.
Conclusion: JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1.
General significance: These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.

JMV 449: a pseudopeptide analogue of neurotensin-(8-13) with highly potent and long-lasting hypothermic and analgesic effects in the mouse

Eur J Pharmacol1992 Aug 25;219(2):327-9.PMID: 1425958DOI: 10.1016/0014-2999(92)90314-t

We recently reported that H-Lys psi (CH2NH)Lys-Pro-Tyr-Ile-Leu-OH (JMV 449), a pseudopeptide analogue of neurotensin-(8-13) with a reduced CH2NH bond in position 8-9, was about 3 times more potent than neurotensin in binding to mouse brain membranes and in contracting the guinea-pig ileum, and was markedly more resistant to degradation than neurotensin when exposed to rat brain membranes. In the present study, we compared the time courses and dose-response relationships for the ability of i.c.v. injected neurotensin and JMV 449 to elicit hypothermia and analgesia (tail-flick test) in the mouse. The results show that the pseudopeptide analogue behaved as a highly potent and long-lasting neurotensin agonist in these two in vivo bioassays. The analogue should prove very useful for studying the effects of chronic neurotensin receptor stimulation in vitro and in vivo.

Neuroprotective effect of the neurotensin analogue JMV-449 in a mouse model of permanent middle cerebral ischaemia

Neurosci Lett2003 Nov 20;351(3):173-6.PMID: 14623134DOI: 10.1016/j.neulet.2003.08.008

The neuroprotective effect of the neurotensin analogue H-Lys-psi(CH2NH)Lys-Pro-Tyr-Ile-Leu-OH (JMV-449) was assessed in a mouse model of permanent distal middle cerebral artery occlusion. Mice were injected with 0.6 nmol JMV-449 or vehicle i.c.v. immediately after ischaemia. The core temperature declined by 6-7 degrees C after 30 min and the hypothermia persisted for 4-5 h. JMV-449 treatment was able to reduce the infarct volume significantly both at 24 h and 14 days after onset of ischaemia. No neuroprotective effect could be seen if the mice were kept normothermic after the JMV-449 treatment suggesting that the neuroprotective effect is mediated via the hypothermia.

Conformational transitions of a neurotensin receptor 1-G i1 complex

Nature2019 Aug;572(7767):80-85.PMID: 31243364DOI: 10.1038/s41586-019-1337-6

Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric Gi1 protein, at a resolution of 3 Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR-Gi/o complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.

Dopamine D2 receptor signaling dynamics of dopamine D2-neurotensin 1 receptor heteromers

Biochem Biophys Res Commun2013 May 24;435(1):140-6.PMID: 23624386DOI: 10.1016/j.bbrc.2013.04.058

Biochemical, histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 (D2R) and neurotensin 1 (NTS1R) receptor-receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor-receptor interactions in Parkinson's disease and schizophrenia. By means of Bioluminiscence Resonance energy transfer (BRET(2)) evidence has for the first time been obtained in the current study for the existence of both D2LR/NTS1R and D2SR/NTS1R heteromers in living HEK293T cells. Through confocal laser microscopy the NTS1R(GFP2) and D2R(YFP) were also shown to be colocated in the plasma membrane of these cells. A bioinformatic analysis suggests the existence of a basic set of three homology protriplets (TVM, DLL and/or LRA) in the two participating receptors which may contribute to the formation of the D2R/NTS1R heteromers by participating in guide-clasp interactions in the receptor interface. The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal. In contrast, the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with ERK1/2 phosphorylation assays. These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor-receptor interactions in the D2LR-NTS1R heteromers at the plasma membrane level (CREB pathway) and synergistic interactions in PKC activation at the cytoplasmatic level (MAPK pathway).