AMPA receptor (EC50 = 4.4 μM).

Compound 5e, also known as AMPA receptor modulator 3, has an EC50 value of 4.4 μM and increases 100 μM L-glutamate-mediated responses in HEK-293 cells expressing iGluR4 Flip.

Enhancement of AMPA receptor (AMPAR) function has emerged as a novel strategy for treatment of depression. Nevertheless, studies on AMPAR function in chronic animal models used to predict antidepressant efficacy are surprisingly lacking. We investigated the role of AMPARs in antidepressant action in an unpredictable chronic mild stress (UCMS) model in BALB/c mice. After 3 wk of UCMS, BALB/c mice developed a number of depressive-like behaviours that were successfully prevented by fluoxetine (20 mg/kg) administration. The AMPAR potentiator LY392098 [N-2-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide] (5 mg/kg), when administered alone, functioned like classic antidepressants by reducing weight loss, fur deterioration and immobility in the tail suspension test. However, LY392098 did not restore sucrose preference and did not reduce anxiety (marble-burying) in stressed mice. In the same protocol, the AMPAR antagonist GYKI (10 mg/kg) reversed most, but not all, of the antidepressant-like actions of fluoxetine. Thus, the antidepressant-like effects of LY392098 were fully predicted by the AMPAR dependence of effects demonstrated for fluoxetine. Our results demonstrate that, in the UCMS paradigm, AMPAR activation exhibits antidepressant-like activity that relates preferentially to specific depressive-like responses and that those specific responses can be defined by their regulation by AMPAR modulation under conditions of stress. [1]

LY392098 (5 mg/kg in saline) was injected intraperitoneally at a volume of 10 ml/kg. A number of studies from our group in rats and mice have shown that there are no behavioural effects upon intraperitoneal injection of 5% DMSO, 5% cremofor, 90% saline vehicle in TST, locomotion and anxiety measures in mice (Crozatier et al.2007; Herzog et al.2008, Tzavara et al.2003, 2006). In addition, previous chronic administration studies from our group have shown that there is no difference in biochemical (Moutsimilli et al.2005, 2008) and behavioural (not shown) outcomes upon repeated administration of different vehicles (5% DMSO, 5% cremofor, 90% saline vs. acidified saline vs. saline) in mice; therefore, vehicle values were pooled and vehicles were treated as a single experimental group in this study. [1]

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Expt 1 [1]
In this experiment we sought to assess the potential antidepressant profile of the AMPA potentiator LY392098, by examining its ability to reverse physical and behavioural alterations induced by chronic stress. The experimental groups compared were (i) control non-stressed, non-treated mice; (ii) stressed-mice treated with vehicle; (iii) stressed mice treated with LY392098 (5 mg/kg).
Physical (weight and fur condition) measurements and behavioural testing were conducted as above.
To ensure that our results are not due to a generalized action of LY392098, the possible effects of repeated treatment with the AMPA potentiator were assessed in non-stressed mice, in a second set of mice. These were control mice that were group-housed (n=4 per cage) and administered with vehicle or LY392098, daily between 12:00 and 14:00 hours for a 3-wk period. Physical (weight and fur condition) measurements and behavioural testing were conducted exactly as for stressed mice as described above and as depicted in Fig. 1b, with the difference that no stress was ever applied.

[1]. Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int J Neuropsychopharmacol. 2010 Oct;13(9):1207-18.

In a 3-week experiment, mice (subjected to stress) were injected daily with the AMPA receptor enhancer LY392098. The dose of LY392098 (5 mg/kg) was selected within the effective dose range for acute antidepressant activity testing (Li et al. 2001, 2003). Compared with the vector control mice, mice treated with LY392098 exhibited milder depressive-like phenotypes under chronic stress. Notably, repeated injections of LY392098 had no effect on unstressed BALB/c mice, suggesting that the effect observed in stressed mice is specific to stress-induced behavioral changes. Specifically, stressed BALB/c mice treated with LY392098 showed significantly reduced depressive-like symptoms compared with BALB/c mice receiving the vector control. Mice treated with the AMPA enhancer experienced less weight loss, healthier fur, and enhanced escape behavior in the forced swimming test (TST) compared to the vector control. These antidepressant-like effects are not due to the nonspecific effects of LY392098 on general activity, as LY392098 did not affect motor performance as measured by an activity meter. Therefore, the effects of LY392098 are similar to those of other types of compounds with antidepressant activity. In fact, commonly used clinical antidepressants, such as fluoxetine and imipramine, as well as potential antidepressant compounds with novel mechanisms of action (e.g., the CRF1 antagonist SSR125543 or the angiotensin antagonist SSR149415) (Griebel et al., 2002; Surget et al., 2008), can prevent stress-induced depressive-like behaviors in chronic stress models. However, LY392098 did not reduce anxiety-like behaviors reflected in the marble-burying latency in stressed BALB/c mice. This is not surprising, as previous studies have shown that AMPA receptor antagonists have anxiolytic effects in rodents (Alt et al., 2006b). The fact that AMPA/algae receptor blockade mediates anxiolytic-like effects while AMPA receptor enhancement induces antidepressant-like effects suggests that different molecular strategies may be needed to treat different symptom clusters of depression. At the doses used, LY392098 did not restore sucrose preference to statistically significant levels in stressed BALB/c mice. The role of AMPA receptors in perceived positive emotional valence and reward is unclear, and the role of AMPA receptors appears to depend on the brain regions studied and the GluR subunits (Todtenkopf et al., 2006). Further experiments using different behavioral paradigms are needed to investigate the effects of AMPA enhancers on hedonic homeostasis and its alterations in depressive states. [1]

C18H22FNO2S

335.436187267303

335.135

C, 64.45; H, 6.61; F, 5.66; N, 4.18; O, 9.54; S, 9.56

211311-39-6

9927707

White to off-white solid powder

4.1

1

4

6

23

452

0

S(C(C)C)(NCC(C)C1C=CC(C2C=CC=CC=2F)=CC=1)(=O)=O

CECANHFDVPUVMI-UHFFFAOYSA-N

InChI=1S/C18H22FNO2S/c1-13(2)23(21,22)20-12-14(3)15-8-10-16(11-9-15)17-6-4-5-7-18(17)19/h4-11,13-14,20H,12H2,1-3H3

N-[2-[4-(2-fluorophenyl)phenyl]propyl]propane-2-sulfonamide

LY-392098; LY 392098; AMPA receptor modulator-3; 211311-39-6; LY392,098; CHEMBL341748; N-{2-[4-(2-fluorophenyl)phenyl]propyl}propane-2-sulfonamide; N-[2-[4-(2-fluorophenyl)phenyl]propyl]propane-2-sulfonamide; LY 392,098; LY392098

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 : ~250 mg/mL (~745.29 mM)

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.)