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.

Abstract

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 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), 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.

• Authors: Feng Liu, Steve Grauer, Cody Kelley, Rachel Navarra, Radka Graf, Guoming Zhang, Peter J Atkinson, Michael Popiolek, Caitlin Wantuch, Xavier Khawaja, Deborah Smith, Michael Olsen, Evguenia Kouranova, Margaret Lai, Farhana Pruthi, Claudine Pulicicchio, Mark Day, Adam Gilbert, Mark H Pausch, Nicholas J Brandon, Chad E Beyer, Tom A Comery, Sheree Logue, Sharon Rosenzweig-Lipson, Karen L Marquis
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 327 Issue 3 Pg. 827-39 (Dec 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 18753411 (Publication Type: Journal Article)

Chemical References

• Antipsychotic Agents
• Oxadiazoles
• Piperidines
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate
• S-(4-fluorophenyl)-(3-(3-(4-fluorophenyl)-(1,2,4)-oxadiazol-5-yl)piperidin-1-yl)methanone

Topics

• Allosteric Regulation (drug effects)
• Animals
• Antipsychotic Agents (pharmacology)
• Avoidance Learning (drug effects)
• Brain Chemistry (drug effects)
• Cell Line
• Cognition (drug effects)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Hippocampus (metabolism)
• Humans
• Oxadiazoles (pharmacology)
• Piperidines (pharmacology)
• Prefrontal Cortex (metabolism)
• Rats
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (drug effects)