LY379268

hmGluR2 (EC50 = 2.69 nM); hmGluR3 (EC50 = 4.48 nM); hmGluR2 (Ki = 14.1 nM); hmGluR3 (Ki = 5.8 nM)

将星形胶质细胞置于 LY379268（0.1 μM；24-48 小时）九周 (9w) 后，线粒体 ROS 水平和细胞凋亡减少，mGlu3R 和 Nrf2 蛋白水平和 SOD 活性增加。在共培养研究中，衰老星形胶质细胞中 mGlu3R 的激活也抑制了 Aβ1-42 诱导的海马神经元损失。当老化星形胶质细胞中的 mGlu3R 被激活时，就会显示出抗氧化作用和保护海马神经元免受 Aβ 诱导的神经毒性的影响 [3]。

就 LY379268 而言，在足底注射角叉菜胶之前给予 3 mg/kg 的剂量，炎症性痛觉过敏的开始被大大延迟，但不会影响爪子炎症 [2]。在用温水将辣椒素皮下注射到用于尾部回缩实验的小鼠尾部之前，给予 LY379268（12 mg/kg；腹膜内注射）以最大程度地减少随之而来的神经源性痛觉过敏 [2]。

---

1.由于缺乏系统活性、选择性配体，先前研究代谢型谷氨酸（mGlu）受体在伤害性加工中的作用受到阻碍。本研究调查了迄今为止在II组mGlu受体上具有全身激动剂活性的最有效化合物LY379268的可能镇痛和/或抗痛觉过敏特性。2.在大鼠身上测试该药物对急性有害刺激的镇痛作用时，LY379268（剂量高达3mg/kg（-1）i.p.）对机械或热刺激的戒断潜伏期没有影响。3.然而，当在板内注射角叉菜胶之前给予3mg/kg（-1）剂量时，与盐水预处理对照组相比，发生的炎性痛觉过敏明显延迟，而不影响爪子的炎症。类似剂量的mGlu非活性对映体LY379267并没有抗痛觉过敏作用。4.在小鼠尾部撤回到温水中的模型中，在皮下注射辣椒素之前给予LY379268（12mg/kg（-1）i.p.），可以减轻随后的神经源性痛觉过敏。5.罗塔棒测试表明，该药物在抗痛觉过敏剂量下不会对大鼠的运动造成损害。6.结果表明，这组mGlu受体的全身激活可以减少炎症和神经源性热痛觉过敏[2]。

作为我们正在进行的旨在鉴定II组代谢型谷氨酸（mGlu）受体高效、选择性和系统活性激动剂的研究计划的一部分，我们制备了新型杂环氨基酸（-）-2-氧杂-4-氨基二环[3.1。0]己烷-4,6-二羧酸酯（LY379268，（-）-9）和（-）-2-硫代-4-氨基二环[3.1.0]己烷-4,5-二羧酸酯。化合物（-）-9和（-）-10在结构上与我们之前描述的纳摩尔效力组II mGlu受体激动剂，（+）-2-氨基二环[3.1.0]己烷-2,6-二羧酸盐一水合物（LY354740一水合物，5）有关，其中5的C4亚甲基单元被氧原子（如（-）-9-中）或硫原子（如在（-）-10-中）取代。化合物（-）-9和（-）-10在大鼠大脑皮质匀浆中有效地立体特异性置换mGlu2/3受体拮抗剂（[3H]LY341495）的特异性结合，IC50值分别为15+/-4和8.4+/-0.8 nM，而在高达100000 nM的浓度下，对NMDA、AMPA或红藻氨酸受体上谷氨酸识别位点的放射配体结合没有影响。化合物（-）-9和（-）-10还有效地取代了表达重组人II组mGlu受体亚型的膜上的[3H]LY341495结合：（-）-9,Ki=14.1+/-1.4 nM在mGlu2和5.8+/-0.64 nM在mHlu3；（-）-10，mGlu2时Ki=40.6+/-3.7 nM，mGlu3时Ki=4.7+/-1.2 nM。评估（-）-9和（-）-10对表达人mGlu受体亚型的非神经元细胞中第二信使反应的功能影响，证明每种亚型都是II组mGlu接收器的高效激动剂：（-）-9,EC50=2.69+/-0.26nM在mGlu2和4.58+/-0.04nM在mGlu3；在mGlu2和7.63+/-2时，EC50=3.91+/-0.81 nM。mGlu3时为08 nM。相比之下，这两种化合物（高达10000 nM）在表达重组人mGlu1a、mGlu5a、mGlu4a或mGlu7a受体的细胞中均未显示出激动剂或拮抗剂活性。然而，（-）-9和（-）-10对II组mGlu受体的激动作用并不完全特异，因为在高纳摩尔浓度下观察到（-）-90的mGlu6激动剂活性（EC50=401+/-46nM），在微摩尔浓度下（EC50=2430+/-600nM）观察到（-10）的mGlu 6激动剂活性；此外，每种在微摩尔浓度下激活mGlu8受体（EC50=1 690+/-130和7 340+/-2 720 nM）。小鼠腹腔注射（-）-9或（-）-10导致非选择性I组/II组mGluR激动剂（1S，3R）-ACPD（（-）-9ED50=19mg/kg，（-）-10ED50=14mg/kg）产生的边缘癫痫发作活动的剂量相关阻断，表明这些分子在全身给药后有效地穿过血脑屏障并抑制I组mGluR介导的边缘兴奋[1]。

星形胶质细胞在氧化应激下为附近的神经元提供抗氧化支持，发挥着关键作用。我们之前已经证明，体外星形胶质细胞亚型3代谢型谷氨酸受体（mGlu3R）具有神经保护作用。然而，它在衰老过程中的作用一直没有得到很好的探索。我们的研究旨在确定mGlu3R激动剂LY379268是否对老年培养的大鼠星形胶质细胞具有抗氧化作用。体外9周（9w）后获得的老年培养星形胶质细胞β-半乳糖苷酶染色呈阳性，mGlu3R和谷胱甘肽（GSH）水平以及超氧化物歧化酶（SOD）活性降低，而核红系因子2（Nrf2）蛋白水平、活性氧（ROS）产生和凋亡增加。用LY379268治疗9w星形胶质细胞导致mGlu3R和Nrf2蛋白水平和SOD活性升高，线粒体ROS水平和凋亡降低。在共培养试验中，老年星形胶质细胞中mGlu3R的激活也阻止了Aβ1-42诱导的海马神经元死亡。我们得出结论，老年星形胶质细胞中mGlu3R的激活具有抗氧化作用，并保护海马神经元免受Aβ诱导的神经毒性。本研究表明，在衰老的星形胶质细胞中激活mGlu3R是一种减缓与年龄相关的神经退行性变的治疗策略[3]。

LY379268 and its mGlu receptor-inactive enantiomer, LY379267 were dissolved in equimolar NaOH and adjusted to a pH of 7 – 9 with equimolar HCl. [2]

---

Experimental design [2]
The experimenter was ‘blind' to the treatment under test. In all tests, ‘control' readings were taken immediately before i.p. injection of either vehicle (saline) or test agent (LY379268 or LY379267) in a volume of 2 ml kg−1, and before the induction of hyperalgesia.

---

Protocol 1 [2]
The analgesic effects of LY379268 or LY379267 were tested on responses to thermal and mechanical stimuli (PWL and PWT) in rats without hind paw inflammation.

---

Protocol 2 [2]
The analgesic effects of LY379268 were tested in mice on TWL to hot water at 50°C. To match protocol 6 below, tests were repeated four times at 3 min intervals 1 h after drug administration.

---

Protocol 3 [2]
The ability of LY379268 to reverse inflammatory hyperalgesia was tested by i.p. injection 3 h after carrageenan injection. Thermal PWL was tested hourly for a further 3 h.

---

Protocol 4 [2]
The ability of LY379268 to prevent the induction of inflammatory hyperalgesia was assessed by administering drug concurrently with carrageenan, after having made baseline readings of PWL. Measurements of thermal PWL were made hourly for the following 4 h.

---

Protocol 5 [2]
As Protocol 4 but drug was administered 1 h before carrageenan was injected into one hind paw. PWLs were then tested hourly for a further 4 h.

---

Protocol 6 [2]
LY379268 or vehicle was given 1 h prior to an injection of capsaicin into the tail of mice. The degree of neurogenic thermal hyperalgesia was tested by TWL to warm water at 47°C. This lower water temperature than for Protocol 2 gave baseline latencies close to cut off so as to maximize the ability to detect hyperalgesia. TWL tests were repeated before and 3, 6 and 9 min after capsaicin.

[1]. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J Med Chem. 1999 Mar 25;42(6):1027-40.

[2]. Systemic pre-treatment with a group II mGlu agonist, LY379268, reduces hyperalgesia in vivo. Br J Pharmacol. 2002 Mar;135(5):1255-62.

[3]. Antioxidant and neuroprotective effects of mGlu3 receptor activation on astrocytes aged in vitro. Neurochem Int. 2020 Nov;140:104837.

LY 379268 is an organic heterobicyclic compound that is (1R,5S)-2-oxabicyclo[3.1.0]hexane carrying amino, carboxy, and carboxy groups at positions 4R, 4R and 6R, respectively. It is a potent agonist of group II metabotropic glutamate receptors mGluR2 and mGluR3 (EC50 = 2.69 nM and 4.48 nM, respectively) that exhibits antipsychotic-like action in animal models of schizophrenia. It has a role as a metabotropic glutamate receptor agonist, a neuroprotective agent, an antipsychotic agent and an anxiolytic drug. It is an organic heterobicyclic compound, a bridged compound and an amino dicarboxylic acid.

---

LY379268 ((−)-9) and LY389795 ((−)-10) are the most potent agonists yet described for group II metabotropic glutamate receptors. The high mGlu2/3 potency and selectivity evinced by these heterobicyclic amino acids lend further experimental evidence supporting the hypothesis that glutamate interacts with mGlu2/3 receptors in a fully extended conformation. Like 5, heterocycles (−)-9 and (−)-10 effectively penetrate into the CNS following systemic administration and block seizures induced by group I mGlu receptor activation. Thus, like 5, these agents may be useful for studying the functions of mGlu2/3 receptors both in vitro and in vivo.[1]

---

In rats, the dose of LY379268 that was anti-hyperalgesic had no effect on rota-rod performance (see also Simmons et al., 1998). However, examination of LY379268 at higher doses was limited due to the induction of exaggerated startle responses. Given that other compounds in this structural series do not show the same effects (unpublished observations), this effect may reflect activity either at other glutamate receptors (perhaps mGlu8, at which LY379268 has activity in vitro; Monn et al., 1999) or at non-glutamate receptors. LY379267, the enantiomer of LY379268, has no agonist or antagonist activity at any mGlu receptor subtype (unpublished data) and in the present study had no anti-hyperalgesic effects, although it did cause an unexplained increase in carrageenan hyperalgesia without affecting baseline values; this is presumably due to an unidentified non-mGlu receptor interaction. In conclusion, this study shows that the systemic activation of group II mGlu receptors can reduce the induction phase of hyperalgesia at doses that do not have motor or other obvious side effects. This lends impetus to the further dissection of the relative roles of mGlu2 and mGlu3 receptor subtypes in the central sensitization process associated with persistent pain.[2]

C7H9NO5

187.15006

187.048

C, 44.92; H, 4.85; N, 7.48; O, 42.74

191471-52-0

10197984

White to off-white solid powder

-4.3

109.85

3

6

2

13

291

4

C1[C@]([C@@H]2[C@H]([C@@H]2O1)C(=O)O)(C(=O)O)N

YASVRZWVUGJELU-MDASVERJSA-N

InChI=1S/C7H9NO5/c8-7(6(11)12)1-13-4-2(3(4)7)5(9)10/h2-4H,1,8H2,(H,9,10)(H,11,12)/t2-,3-,4+,7+/m1/s1

(1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY379268; LY 379268; 191471-52-0; (1R,4R,5S,6R)-4-Amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY-379268; 2-Oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid, 4-amino-, (1R,4R,5S,6R)-; CHEMBL275079; S96JF4J697; LY-379268.

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)

0.1 M NaOH : ~200 mg/mL (~1068.66 mM)
H2O : ~2 mg/mL (~10.69 mM)

配方 1 中的溶解度: 25 mg/mL (133.58 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

---

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。