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KI0365LY4040395 mg$112
LY40403925 mg$432
LY40403950 mg$752

Chemical Characteristic

Product NameLY404039
SynonymsLY2140023
CAS No.635318-11-5
Molecular Weight 235.22
FormulaC7H9NO6S
Chemical Name(1R,4S,5S,6S)-4-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-2,2-dioxo-2?6-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid
Smiles[C@@]1(CS(=O)(=O)[C@@H]2[C@H]1[C@H]2C(=O)O)(C(=O)O)N
Chemical Structure

Biological activities

LY404039 is a potent and selective group II metabotropic glutamate (mGlu2 and mGlu3) receptor agonist. LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors with Ki values of 149 and 92 nM, respectively, and in rat neurons expressing native mGlu2/3 receptors with Ki of 88 nM. Thus, LY404039 is equipotent to LY354740 at human mGlu3 receptors and in rat brain but slightly less potent at human mGlu2 receptors. LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibits forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. LY404039 suppresses electrically evoked excitatory activity in the striatum, and serotonin-induced L-glutamate release in the prefrontal cortex. LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders, and works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. At the same time, LY404039 demonstrates higher plasma exposure and better oral bioavailability in pharmacokinetic experiments.[1] Meanwhile, LY404039 is the first apparently non-dopamine-interfering effective drug for psychosis. LY404039 inhibits the binding of the D2-specific antagonist, [3H] domperidone, to the human cloned D2 receptor with dissociation constants of 8.2 nM at D2High and 1.64 μM at D2Low. Using rat striatal tissue, LY404039 has dissociation constants of 12.6 nM at D2High and 2.1 μM at D2Low. [2] In wild-type mice, LY404039 (3??0 mg/kg i.p.) significantly reverses d-amphetamine (AMP) (5 mg/kg, i.p.)-induced increases in ambulations, and reduces time spent at rest. [3]

Protocols

Stock solutions of 10 mM LY404039 in DMSO are aliquoted and stored at −20 °C until the day of recording. [1]

References

[1] Rorick-Kehn LM, et al. 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). J Pharmacol Exp Ther. 2007, 321(1): 308-317.
[2] Philip S, et al. An agonist at glutamate and dopamine D2 receptors, LY404039. Neuropharmacology, 2012, in press.
[3] Fell MJ, et al. Evidence for the role of metabotropic Glutamate (mGlu) 2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1 R, 4S, 5S, 6S) - 4- Amino-2-sulfonylbicyclo [3.1.0] hexane- 4, 6- dicarboxylic acid (LY404039). J Pharmacol Exp Ther, 2008, 326: 209-217.

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