Uses
LY 2140023 is a drug developed as a treatment option for schizophrenia. It targets the mGlu2/3 receptor once metabolized.
Definition
ChEBI: LY404039 is an organic heterobicyclic compound that is (1S,5R)-2-thiabicyclo[3.1.0]hexane carrying oxo, oxo, amino, carboxy, and carboxy groups at positions 2, 2, 4S, 4S, and 6S, respectively. It is a potent agonist of group II metabotropic glutamate receptors mGluR2 mGluR3 (Ki = 149 nM and 92 nM, respectively) and exhibits antipsychotic and anxiolytic efficacy in animal models. It has a role as a metabotropic glutamate receptor agonist, an antipsychotic agent, an anxiolytic drug and a dopamine agonist. It is a dicarboxylic acid, a bridged compound, an organic heterobicyclic compound, a sulfone and a non-proteinogenic amino acid derivative.
Biological Activity
ly404039 is a potent and highly selective agonist of recombinant human mglu2 and mglu3 receptors and rat neurons expressing native mglu2/3 receptor with ki values of 149, 92 and 88 nm, respectively [1].the inhibition of forskolin-stimulated camp formation has indicated that ly404039 was a nanomolar potent agonist of human mglu2 (ec50 = 23 nm) and mglu3 (ec50 = 48 nm) receptors. additionally, ly404039 could concentration-dependently decrease excitatory postsynaptic potentials (epsps) in rat striatal spiny neuron (ec50 = 141 nm). ly404039 has also been reported to suppress the frequency of 5-ht-induced postsynaptic currents (ec50 = 82.3 nm) in rat prefrontal cortical slices [1].
in vivo
LY404039 attenuates amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibits conditioned avoidance responding. LY404039 also reduces fear-potentiated startle in rats (3-30 μg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. LY404039 (10 mg/kg) also increases dopamine and serotonin release/turnover in the prefrontal cortex[3].
Following oral administration of LY404039 to fasted rats at doses of 1, 3, or 10 mg/kg, exposure increased proportionally with dose. LY404039 (10 mg/kg; p.o.) treatment shows the Cmax is 1528.5 ng/mL and Tmax is 2 hours in rats[1].
IC 50
mGlu2 Receptor: 149 nM (Ki, Recombinant human mGluR2); hmGluR3: 92 nM (Ki)
References
[1] rorick-kehn lm1, johnson bg, burkey jl, wright ra, calligaro do, marek gj, nisenbaum es, catlow jt, kingston ae, giera dd, herin mf, monn ja,mckinzie dl, schoepp dd. 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 apr;321(1):308-17. epub 2007 jan 4. j pharmacol exp ther. 2007 apr;321(1):308-17. epub 2007 jan 4.
