| Target Validation Information | |||||
|---|---|---|---|---|---|
| TTD ID | T02719 | ||||
| Target Name | Metabotropic glutamate receptor 3 (mGluR3) | ||||
| Type of Target |
Clinical trial |
||||
| Drug Potency against Target | LY-544344 | Drug Info | IC50 = 11~38 nM | [3] | |
| LY354740 | Drug Info | IC50 = 11~38 nM | [3] | ||
| LY-379268 | Drug Info | Ki = 5.8 nM | [1] | ||
| LY-389795 | Drug Info | Ki = 4.7 nM | [1] | ||
| [3H]quisqualate | Drug Info | IC50 = 25 nM | [2] | ||
| Action against Disease Model | LY404039 | Drug Info | We use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine(PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 mg/kg, i.p.)-induced increases in ambulations, distance traveled, and reduced time spent at rest. LY404039 reversed PCP (7.5 mg/kg i.p.)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 (10 mg/kg i.p.) on PCP and AMP-evoked behavioral activation were absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice, indicating that the activation of mGlu2 and not mGlu3 receptors is responsible for the antipsychotic-like effects ofthe mGlu2/3 receptor agonist LY404039 | [4] | |
| References | |||||
| REF 1 | Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identif... J Med Chem. 2007 Jan 25;50(2):233-40. | ||||
| REF 2 | Excitatory amino acid receptor ligands: resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)... J Med Chem. 1998 Mar 12;41(6):930-9. | ||||
| REF 3 | Positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (mGluR2). Curr Top Med Chem. 2005;5(9):869-84. | ||||
| REF 4 | 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). J Pharmacol Exp Ther. 2008 Jul;326(1):209-17. | ||||
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