Metabotropic glutamate receptor (mGluR)
Metabotropic glutamate receptors (mGluRs), specifically group II mGluRs (mGlu2 and mGlu3) with high affinity, and also group I (mGlu1a, mGlu5a) and group III (mGlu4, mGlu7, mGlu8) with lower affinity. mGluRs are G protein-coupled receptors that modulate synaptic transmission in the central nervous system. LY341495 is a potent orthosteric antagonist that competes with glutamate for binding at the orthosteric site of these receptors. LY341495 is highly potent and selective for group II mGluRs (mGlu2/3).

Effects of LY341495 on Akt and Wnt pathway proteins [2]
The mGlu2/3 antagonist LY341495 was used to examine the effects of blocking the mGlu2/3 on Akt and Wnt pathway proteins. Repeated treatment with 3.0 mg/kg of LY341495 decreased Dvl-2, pGSK-3α/β and β-catenin protein levels but Dvl-1, Dvl-3 and GSK-3α/β were unaffected in both the PFC and STR (Fig. 3a and b). In addition, to changes in the Wnt proteins, a reduction in pAkt Ser473 but not in total Akt or pAkt Thr308 were observed in the PFC and STR (Fig. 3c and d). A lower dose of repeated LY341495 (1.0 mg/kg) was also used and had no effect on Akt or Wnt pathway proteins tested in the PFC or STR (data not shown). Finally, changes in Akt and Wnt pathway proteins were assessed following acute administration of LY341495. Decreases in pGSK-3α/β (Fig. 4a and b) and pAkt Ser473 (Fig. 4c and d) were observed in the PFC and STR following acute administration of LY341495 (3.0 mg/kg). Therefore, acute administration of LY341495 decreased pAkt and pGSK-3 levels but repeated treatment (3.0 mg/kg) is needed to reduce β-catenin levels. Furthermore, LY341495 had the generally the opposite effect following acute and chronic administration compared to mGlu2/3 agonist, LY379268.

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LY341495 is a metabotropic glutamate receptor (mGluR) antagonist with IC50s of 21 nM for mGlu2, 14 nM for mGlu3, 7.8 microM for mGlu1a, 8.2 microM for mGlu5a, 170 nM for mGlu8, 990 nM for mGlu7, and 22 microM for mGlu4 receptors. In functional assays, LY341495 potently blocks the ability of group II mGluR agonists (e.g., LY379268 or DCG-IV) to inhibit forskolin-stimulated cAMP accumulation. (Rac)-LY341495 is the inactive isomer and is used as a negative control to validate that observed biological effects are mediated by specific mGluR antagonism.

LY341495 (0.3, 1 and 3 mg/kg, ip) exhibits lower levels of insight into the state [1]. LY341495 (3.0 mg/kg) reduced Dvl-2, pGSK-3α/β and β-catenin protein levels, but Dvl-1, Dvl-3 and GSK-3α/β were not activated in PFC and STR. Compared with the mGlu2/3 stimulant LY379268, LY341495 generally produces just the right effect after fast and fast[2]. c-Fos expression induced by LY341495 (3 mg/kg, i.p., 2.5 hours) was not altered in either KO brain. In mGluR3-KO, LY341495 has little activity in the central extended amygdala [central amygdala] nucleus, nucleus of cancellation (CeL) and bed nucleus of stria terminalis, dorsal nucleus (BSTLD) [3].

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Experimental evidence suggests that metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists affect cognitive function, although contradictory findings have been reported. To clarify the role of mGlu2/3 receptor antagonists in one aspect of cognition, the present study investigated the effects of a broad range of doses of the mGlu2/3 receptor antagonist LY341495 on post-training recognition memory components (storage and/or retrieval) in rats. The efficacy of LY341495 in antagonizing the extinction of recognition memory was also investigated. The novel object recognition test was used as the memory test. The highest LY341495 doses administered (0.3, 1, and 3 mg/kg) disrupted performance in this recognition memory procedure in rats at all delay conditions tested, whereas administration of lower doses (0.05 and 0.1 mg/kg) did not impair recognition memory. Moreover, administration of the low LY341495 doses (0.05 and 0.1 mg/kg) counteracted the extinction of recognition memory. The present results indicate that administration of the mGlu2/3 receptor antagonist LY341495 can either impair or enhance recognition memory in rats, depending on the dose of the compound and delay period used. Thus, together with previously reported findings, the present data suggest complex effects of this compound on cognitive function, particularly recognition memory.[1]

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No in vivo activity data is provided for (Rac)-LY341495 itself, as it is intended as an experimental control. The active parent compound LY341495 has been extensively studied in animal models of neurological and psychiatric disorders. In behavioral pharmacology studies, LY341495 (administered systemically or intracerebrally) has been shown to have procognitive effects, modulate anxiety and depression-like behaviors, and affect memory formation. LY341495 is also used to block mGlu2/3 receptors in studies of synaptic transmission and plasticity. (Rac)-LY341495 is used as a negative control in these in vivo experiments.

For non-cell receptor binding assays, membranes from BHK cells expressing recombinant human mGlu receptors (mGlu2, mGlu3, mGlu1a, mGlu5a, mGlu4, mGlu7, mGlu8) are prepared. The membranes are incubated with the radioligand [3H]LY341495 (1-5 nM) or [3H]glutamate (10-50 nM) and varying concentrations of test compound (0.01 nM to 100 uM) in assay buffer (50 mM Tris-HCl, pH 7.4, 2.5 mM CaCl2, 5 mM MgCl2) at 4degC for 60-120 minutes. Bound and free radioligand are separated by rapid filtration through GF/B filters pretreated with 0.3% PEI. Radioactivity is counted, and IC50 values are calculated using the Cheng-Prusoff equation. Ki values are determined from IC50 values and the Kd of the radioligand.

A functional cAMP accumulation assay is performed in CHO or HEK293 cells stably expressing human mGlu2 or mGlu3 receptors. Cells are seeded in 96-well plates and pre-incubated with 1 mM IBMX (phosphodiesterase inhibitor) for 30 minutes. To measure antagonist activity, cells are treated with varying concentrations of LY341495 or (Rac)-LY341495 as control (0.01 nM to 10 uM) in the presence of a fixed concentration of a group II mGluR agonist (e.g., LY379268 10-100 nM) and 1-10 uM forskolin. After 30-60 minutes, cAMP levels in cell lysates are measured using a competitive ELISA or HTRF-based kit. (Rac)-LY341495 is used as a negative control. For in vivo studies, the active compound LY341495 is typically administered intraperitoneally (IP) in rats or mice at doses of 0.1-10 mg/kg. LY341495 is dissolved in a vehicle such as saline or 0.1% DMSO in saline. Behavioral testing (e.g., novel object recognition, forced swim test, elevated plus maze) is performed 30-60 minutes post-injection. Cannulated animals can receive intracerebral microinjections (1-10 ug/site) of LY341495 directly into specific brain regions (e.g., prefrontal cortex, hippocampus, amygdala). (Rac)-LY341495 is used as a control.

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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LY341495 is soluble in DMSO at 2.5 mg/mL (7.07 mM; requires ultrasonic and warming and heat to 60degC). For in vivo studies, it can be formulated in sterile saline containing a small percentage of DMSO or in 1% Tween 80 in saline. The active parent compound LY341495 is a potent and selective group II mGluR antagonist with good brain penetration after systemic administration. Detailed PK parameters such as half-life, bioavailability, and clearance are not publicly available. (Rac)-LY341495 is expected to have similar PK properties but no target engagement. Storage: Powder -20degC for 3 years; In solvent -80degC for 6 months or -20degC for 1 month.

As an inactive isomer, (Rac)-LY341495 is non-toxic at the concentrations used for control experiments (typically low uM range in vitro or 0.1-10 mg/kg in vivo). The active parent compound LY341495 is well-tolerated in rodents at doses up to 10 mg/kg IP, with no significant weight loss or overt signs of toxicity. No hepatotoxicity, nephrotoxicity, or neurotoxicity has been reported at these doses. Comprehensive toxicology studies, including chronic toxicity and genotoxicity, have not been published for this research tool compound. Standard laboratory safety precautions should be followed.

LY341495 is a research-grade pharmacological tool for studying metabotropic glutamate receptor (mGluR) function, particularly for group II mGluRs (mGlu2 and mGlu3). LY341495 has been instrumental in elucidating the roles of mGlu2/3 receptors in synaptic transmission, learning and memory, anxiety, depression, addiction, and schizophrenia. The compound is widely used in neuroscience research to block mGlu2/3 receptors either systemically or via intracerebral microinjection. Key references: Kingston AE, et al. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology. 1998;37(1):1-12. (Rac)-LY341495 is the inactive isomer used as a control. This product is for research use only and is not FDA-approved for human therapy.

[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.

Neuropathic pain remains a clinical challenge due to its unclear mechanisms and wide range of clinical manifestations. Matrix metalloproteinases (MMPs)-9 and MMP-2 have been identified as key components of neuropathic pain because they promote the maturation of inflammatory cytokines and induce neuroinflammation. Therefore, inhibiting MMPs may be a novel approach to treating neuropathic pain. This study found that the widely used respiratory drug N-acetylcysteine (NAC) significantly alleviates neuropathic pain through a unique MMP-inhibiting mechanism. Both in vitro (0.1 mM) and in vivo administration of NAC significantly inhibited the activity of MMP-9/2. Oral administration of NAC (50, 100, and 200 mg/kg) not only delayed the onset of chronic compression injury (CCI)-induced neuropathic pain in rats but also inhibited its persistence. Administration of NAC blocked the maturation of interleukin-1β (a key substrate of MMPs) and significantly inhibited CCI-induced neuronal activation, including inhibiting the phosphorylation of protein kinases Cγ, NMDAR1, and mitogen-activated protein kinase. In addition, NAC significantly inhibited CCI-induced microglial activation, but had no significant effect on astrocytes. These results indicate that NAC is an effective and safe treatment that can relieve neuropathic pain by potently inhibiting MMP activation, and it has been used clinically. [4]

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C20H19NO5

353.37

353.126

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

LY341495;201943-63-7

10713043

White to off-white solid powder

-0.2

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

(Rac)-LY341495; LY 341495; SCHEMBL24606222;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)