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ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N -methyl- d -aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [ S -(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin...
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Published in: | The Journal of pharmacology and experimental therapeutics 2008-12, Vol.327 (3), p.827-839 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N -methyl- d -aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [ S -(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent
and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca 2+ assays (EC 50 = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted
mGlu5 receptor glutamate response curve to the left (9-fold at 1 μM) and competed for binding of [ 3 H]2-methyl-6-(phenylethynyl)pyridine ( K i = 4.3 μM), but not [ 3 H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein
phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction
mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal
effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little
effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor
activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not
in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced
impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are
consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic
and procognitive agents. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.108.136580 |