LY-341495

mGluR1a ( IC50 = 7.8 μM ); mGluR2 ( IC50 = 21 nM ); mGluR3 ( IC50 = 14 nM ); mGluR4 ( IC50 = 22 μM ); mGluR5a ( IC50 = 8.2 μM ); mGluR7 ( IC50 = 990 nM ); mGluR8 ( IC50 = 170 nM )

LY341495对Akt和Wnt通路蛋白的影响[2]
使用mGlu2/3拮抗剂LY341495检测阻断mGlu2/3对Akt和Wnt通路蛋白的影响。Repeated treatment with 3.0 mg/kg的LY341495降低了PFC和STR中Dvl-2、pGSK-3α/β和β-catenin蛋白水平，但Dvl-1、Dvl-3和GSK-3α/μ不受影响（图3a和b）。此外，对于Wnt蛋白的变化，在PFC和STR中观察到pAkt Ser473的减少，但Akt或pAkt Thr308的总量没有减少（图3c和d）。还使用了较低剂量的重复LY341495（1.0mg/kg），对PFC或STR中测试的Akt或Wnt通路蛋白没有影响（数据未显示）。最后，评估急性施用LY341495后Akt和Wnt通路蛋白的变化。急性给药LY341495（3.0 mg/kg）后，PFC和STR中pGSK-3α/β（图4a和b）和pAkt Ser473（图4c和d）的含量降低。因此，急性给药LY341495可降低pAkt和pGSK-3水平，但需要重复治疗（3.0mg/kg）以降低β-catenin水平。此外，与mGlu2/3激动剂LY379268相比，LY341495在急性和慢性给药后的效果通常相反。

LY341495 (0.3、1 和 3 mg/kg，ip) 在状态中表现出较低水平的洞察能力[1]。LY341495 (3.0 mg/kg) 降低 Dvl-2、pGSK-3α/β 和 β-catenin蛋白水平，但 Dvl-1、Dvl-3 和 GSK-3α/β 在 PFC 和 STR 中均不步行。与 mGlu2/3 兴奋剂 LY379268 相比，LY341495 在快速和快速后通常会产生正好的效果[2]。LY341495 (3 mg/kg，腹腔注射，2.5小时)诱导c-Fos表达在任一KO脑中均未改变。在mGluR3-KO中，LY341495在中央扩展杏仁核[杏仁核中央]核、取消核 (CeL) 和终纹床核、背侧核 (BSTLD) 中几乎没有活性[3]。

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实验证据表明，代谢型谷氨酸2/3（mGlu2/3）受体拮抗剂会影响认知功能，尽管有相互矛盾的发现。为了阐明mGlu2/3受体拮抗剂在认知的一个方面的作用，本研究调查了大剂量mGlu2/3拮抗剂LY341495对大鼠训练后识别记忆成分（储存和/或检索）的影响。还研究了LY341495对抗识别记忆消失的功效。新的物体识别测试被用作记忆测试。在所有测试的延迟条件下，施用最高剂量的LY341495（0.3、1和3 mg/kg）会破坏大鼠在这种识别记忆过程中的表现，而施用较低剂量（0.05和0.1 mg/kg）则不会损害识别记忆。此外，低剂量LY341495（0.05和0.1mg/kg）的给药抵消了识别记忆的消失。目前的结果表明，mGlu2/3受体拮抗剂LY341495的给药可以损害或增强大鼠的识别记忆，具体取决于化合物的剂量和使用的延迟时间。因此，结合之前报道的发现，目前的数据表明，这种化合物对认知功能，特别是识别记忆有复杂的影响。[1]

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LY341495是一种代谢型谷氨酸受体（mGluR）拮抗剂，对mGluR2/3显示出选择性，但在10-1000倍的浓度下，对所有mGluR亚型都有可测量的拮抗效果。在啮齿动物体内，它增加了运动活动和觉醒，增强了认知能力，调节了情绪。它还诱导了广泛的神经元激活，以c-Fos表达来衡量。为了进一步研究LY341495在体内可能起作用的受体亚型，我们分析了其在mGluR2敲除（KO）和mGluR3敲除脑中的作用是如何改变的。在大多数地区，LY341495（3mg/kg，腹腔注射，2.5小时）诱导的c-Fos表达在两个KO脑中都没有改变。然而，在mGluR3 KO小鼠中，LY341495在中央延伸杏仁核[杏仁核中央核、外侧核（CeL）和终纹床核、侧脊核（BSTLD）]中几乎不活跃，这表明mGluR3的急性阻断正在激活野生型大脑中的这些神经元。在丘脑腹外侧核（VL）中，LY341495在mGluR3 KO小鼠中产生了显著增强的反应，在mGluR2 KO小鼠中减弱了反应。我们还分析了在熟悉环境中的运动，发现无论基因型如何，LY341495（1-30mg/kg，i.p.）都能剂量依赖性地增加运动活性。在不熟悉的环境中，两种KO菌株对LY341495的敏感性都有所提高，可以减少运动习惯。我们的研究结果表明，LY341495的某些作用可能不是通过阻断mGluR2或mGluR3介导的，而是可能涉及其他mGluR亚型。或者，mGluR2和mGluR3的功能可能是多余的，无论LY341495在体内拮抗哪种受体亚型，都会产生类似的效果。[3]

在非神经元（RGT，大鼠谷氨酸转运体）细胞中表达的人重组代谢型谷氨酸（mGlu）受体亚型上研究了结构新颖的化合物LY341495的体外药理学。LY341495是1S，3R-1-氨基环戊烷-1,3-二羧酸（ACPD）诱导的抑制毛喉素刺激的mGlu2和mGlu3受体cAMP形成的纳摩尔强效拮抗剂（相应的IC50分别为0.021和0.014微M）。在I组表达mGlu受体的细胞中，LY341495在拮抗奎奎奎特酸诱导的磷酸肌醇（PI）水解方面具有微摩尔的效力，mGlu1a和mGlu5a受体的IC50值分别为7.8和8.2微摩尔。在人类III组mGlu受体中，LY341495在mGlu8处对L-2-氨基-4-膦酰基丁酸（L-AP4）反应的抑制作用最强，IC50为0.17微M。LY341495对mGlu7的效力较低（IC50=0.99微M），对mGlu4的效力最低（IC50=22微M）。大鼠脑膜的结合研究还表明，II族mGlu受体对LY341495具有纳摩尔级的强效亲和力，离子型谷氨酸受体配体结合没有明显的位移。因此，LY341495在mGlu受体亚型中具有独特的选择性范围，其效力顺序为mGlu3>或=mGlu2>mGlu8>mGlu7>>mGlu1a=mGlu5a>mGlu4。特别是，LY341495是迄今为止报道的mGlu2、3和8受体最有效的拮抗剂。因此，它代表了一种新的药理学试剂，用于阐明mGlu受体在实验系统中的功能[5]。

蛋白质印迹[2]
如前所述，对PFC和STR进行蛋白质分离、定量和蛋白质印迹（Alimohamad等人，2005a）。使用灰度校准扫描仪和柯达分子成像软件从X射线胶片上获得密度值。对α-微管蛋白的密度测定值进行校正，并表示为对照的百分比。使用学生t检验对数据进行统计显著性分析。

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共免疫沉淀[2]
使用添加了蛋白酶和磷酸酶抑制剂的非变性裂解缓冲液从未用药大鼠或用LY379268（3mg/kg，i.p.）治疗的大鼠的PFC中分离蛋白质（n=6只大鼠/实验）。使用ExactCruz系统进行免疫沉淀（IP），500μg蛋白质和mGlu2/3（4μg/IP）或Dvl-2（4μg/IP）抗体，如前所述（Sutton等人，2007）。使用来自同一物种的非特异性IgG代替IP抗体进行阴性对照。对IP样品进行蛋白质印迹，并检测感兴趣的蛋白质；Dvl-2（1:100），Dvl-3（圣克鲁斯生物技术公司；1:100），葛兰素史克第三集团（1:300）阿克特（1:1250）。

Six experimental groups (each with ten rats) are created by randomly assigning the rats: vehicle and 0.05, 0.1, 0.3, 1, and 3 mg/kg LY341475. The LY341495 doses are selected on the basis of results from previous Published studies that evaluated the effects of this compound on cognition. Training: Two 2-minute trials were given to the rats during the training session. Right after T1, the animals are given either LY341495 or the vehicle. Given that untreated control rats in these experiments still have intact recognition memory, an ITI of one hour is employed with a 2-min trial duration.

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Locomotor activity [2]
Horizontal locomotor activity was recorded from rats treated with LY341495 (1.0 and 3.0 mg/kg, i.p.) or an appropriate vehicle following a single injection or following five consecutive daily injections (n = 12 rats/treatment). In a separate set of experiments, rats were treated once or daily for five consecutive days with LY341495 (3.0 mg/kg, i.p.) or vehicle followed 5 min later by the administration of the GSK-3 inhibitor, SB216763 (3.0 mg/kg, i.p.) or vehicle (n = 8 rats/treatment). The dose of SB216763 was selected based on previous studies showing that treatment attenuated hyperlocomotion in DAT-KO mice at 3.0 mg/kg (Beaulieu et al. 2004). Horizontal locomotor activity was recorded on day 1 and day 5 and all experiments were conducted in the light phase between 9:00 and 13:00 hours. Horizontal locomotor activity was recorded using Med Associates activity monitor chambers and software for 60 min. Data was analyzed using a one-way anova or two-way anova followed by the Newman-Keuls post hoc test.

[1]. The metabotropic glutamate 2/3 receptor antagonist LY341495 differentially affects recognition memory in rats. Behav Brain Res. 2012 May 1;230(2):374-9.

[2]. Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268.J Neurochem. 2011 Jun;117(6):973-83.

[3]. Use of MGLUR2 and MGLUR3 knockout mice to explore in vivo receptor specificity of the MGLUR2/3 selective antagonist LY341495. Neuropharmacology. 2009 Aug;57(2):172-82. Epub 2009 May 27.

[4]. N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases. Pain. 2016 Aug;157(8):1711-23.

[5]. LY341495 Is a Nanomolar Potent and Selective Antagonist of Group II Metabotropic Glutamate Receptors.Neuropharmacology. 1998;37(1):1-12.

(1S,2S)-2-[(1S)-1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl]-1-cyclopropanecarboxylic acid is a member of xanthenes.

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Metabotropic glutamate receptors 2/3 (mGlu(2/3)) have been implicated in schizophrenia and as a novel treatment target for schizophrenia. The current study examined whether mGlu(2/3) regulates Akt (protein kinase B) and Wnt (Wingless/Int-1) signaling, two cascades associated with schizophrenia and modified by antipsychotics. Western blotting revealed increases in phosphorylated Akt (pAkt) and phosphorylated glycogen synthase kinase-3 (pGSK-3) following acute and repeated treatment of LY379268 (mGlu(2/3) agonist), whereas increases in dishevelled-2 (Dvl-2), dishevelled-3 (Dvl-3), GSK-3 and β-catenin were only observed following repeated treatment. LY341495 (mGlu(2/3) antagonist) induced the opposite response compared with LY379268. Co-immunoprecipitation experiments showed an association between the mGlu(2/3) complex and Dvl-2 providing a possible mechanism to explain how the mGlu(2/3) can mediate changes in Wnt signaling. However, there was no association between the mGlu(2/3) complex and Akt suggesting that changes in Akt signaling following LY341495 and LY379268 treatments may not be directly mediated by the mGlu(2/3) . Finally, an increase in locomotor activity induced by LY341495 treatment correlated with increased pAkt and pGSK-3 levels and was attenuated by the administration of the GSK-3 inhibitor, SB216763. Overall, the results suggest that mGlu(2/3) regulates Akt and Wnt signaling and LY379268 treatment has overlapping effects with D(2) dopamine receptor antagonists (antipsychotic drugs).[2]

C20H19NO5

353.36856

353.126

C, 67.98; H, 5.42; N, 3.96; O, 22.64

201943-63-7

(Rac)-LY341495

9819927

White to off-white solid powder

1.4±0.1 g/cm3

580.8±40.0 °C at 760 mmHg

305.1±27.3 °C

0.0±1.7 mmHg at 25°C

1.669

2.53

109.85

3

6

5

26

559

3

O=C(O)[C@@H]1[C@H](C1)[C@@](N)(CC2C3=C(C=CC=C3)OC4=C2C=CC=C4)C(O)=O

VLZBRVJVCCNPRJ-KPHUOKFYSA-N

InChI=1S/C20H19NO5/c21-20(19(24)25,15-9-13(15)18(22)23)10-14-11-5-1-3-7-16(11)26-17-8-4-2-6-12(14)17/h1-8,13-15H,9-10,21H2,(H,22,23)(H,24,25)/t13-,15-,20-/m0/s1

(1S,2S)-2-[(1S)-1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl]cyclopropane-1-carboxylic acid

LY 341495; LY-341495; 201943-63-7; (2S)-2-AMINO-2-[(1S,2S)-2-CARBOXYCYCLOPROP-1-YL]-3-(XANTH-9-YL) PROPANOIC ACID; 2-[(1s,2s)-2-Carboxycyclopropyl]-3-(9h-Xanthen-9-Yl)-D-Alanine; (1S,2S)-2-[(1S)-1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl]cyclopropane-1-carboxylic acid; 9H-Xanthene-9-propanoic acid, alpha-amino-alpha-[(1S,2S)-2-carboxycyclopropyl]-, (alphaS)-; LY341495

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~6 mg/mL (~17 mM)

配方 1 中的溶解度: ≥ 0.6 mg/mL (1.70 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 6.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。