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 Ca2+ assays (EC50 = 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 [3H]2-methyl-6-(phenylethynyl)pyridine (Ki = 4.3 μM), but not [3H]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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.136580.
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ABBREVIATIONS: mGlu, metabotropic glutamate receptor; GPCR, G-protein-coupled receptor; PAM, positive allosteric modulator; CPPHA, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide; CDPPB, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)-benzamide; ADX47273, S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone; NMDA, N-methyl-d-aspartate; MPEP, 2-methyl-6-(phenylethynyl)pyridine; MK-801, (5R,10S)-(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cylc ohepten-5,10-imine; ERK, extracellular signal-regulated kinase; CREB, cAMP-response element binding; PCP, phencyclidine; 5-CSRT, five-choice serial reaction time; MTEP, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine; FLIPR, fluorometric imaging plate reader; HEK, human embryonic kidney; DMSO, dimethyl sulfoxide; l-AP4, l-(+)-2-amino-4-phosphonobutyric acid; ANOVA, analysis of variance; MED, minimal effective dose; ITI, intertrial interval; SD, stimulus duration; LY379268, (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate.
- Received January 16, 2008.
- Accepted August 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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