LY404039 is a selective agonist for the metabotropic glutamate receptor (mGluR)2/3 receptors. mGluR2 acts as a glutamatergic autoreceptor in the brain regions that are believed to be important in the pathophysiology of schizophrenia, such as the prefrontal cortex, striatum, hippocampal formation and the thalamus. LY404039 potently inhibits forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. LY404039 reduces responding on the EtOH in the pavlovian spontaneous recovery (PSR) test and reduces the expression of an alcohol deprivation effect (ADE) during relapse, but does not affect EtOH responding under maintenance conditions. LY404039 also increases dopamine and serotonin release/turnover in the prefrontal cortex.
|Cell lines||RGT cells expressing human mGlu receptors|
|Preparation method||For cAMP assays, cells expressing human mGlu2, mGlu3, mGlu4, mGlu6, mGlu7, or mGlu8 were washed (two times with 200 μl/well) with assay medium (Dulbecco's phosphate-buffered saline plus 3 mM glucose and 500 μM isobutymethylxanthine). The media were replaced with 0.2 ml/well of the same solution, and cells were preincubated for 30 min at 37°C under 95% O2, 5%CO2. Each well was then washed two successive times with 200 μl of medium. Compounds of interest or water vehicle were added, along with forskolin solution (15 μM final concentration group II mGlu receptors, 1 μM final concentration group III mGlu receptors, and total incubation volume 0.1 ml), and cells were further incubated at 37°C under 95% O2, 5%CO2 for 20 min. The incubation was terminated by adding 0.1 ml of 0.2% Triton X-100 lysing solution. Levels of cAMP were determined by a cAMP-125I Scintillation Proximity Assay Screening Biotrak Assay kit (GE Healthcare).|
|Incubation time||20 min|
|Animal models||PCP-Induced mouse model|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039).
Fell MJ, et al. J Pharmacol Exp Ther. 2008 Jul;326(1):209-17. PMID: 18424625.
In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders.
Rorick-Kehn LM, et al. Psychopharmacology (Berl). 2007 Jul;193(1):121-36. PMID: 17384937.
Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039).
Rorick-Kehn LM, et al. J Pharmacol Exp Ther. 2007 Apr;321(1):308-17. PMID: 17204749.
The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats.
Rodd ZA, et al. Behav Brain Res. 2006 Aug 10;171(2):207-15. PMID: 16678921.
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