Abstract
Previous studies indicate that agonists of the group II metabotropic glutamate receptors (mGluRs), mGluR2 and mGluR3, may provide a novel approach for the treatment of anxiety disorders and schizophrenia. However, the relative contributions of the mGluR2 and mGluR3 subtypes to the effects of the group II mGluR agonists remain unclear. In the present study, we describe an alternate synthesis and further pharmacological characterization of a recently reported positive allosteric modulator of mGluR2 termed biphenyl-indanone A (BINA). In recombinant systems, BINA produced a robust and selective potentiation of the response of mGluR2 to glutamate with no effect on the glutamate response of other mGluR subtypes. In hippocampal brain slices, BINA (1 μM) significantly potentiated the mGluR2/3 agonist-induced inhibition of excitatory synaptic transmission at the medial perforant path-dentate gyrus synapse. BINA was also efficacious in several models predictive of antipsychotic- and anxiolytic-like activity in mice. The behavioral effects of BINA were blocked by the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), suggesting that the in vivo effects of BINA are mediated by increased activation of mGluR2. Collectively, these results indicate that BINA is a selective mGluR2 positive allosteric modulator and provide further support for the growing evidence that selective allosteric potentiators of mGluR2 mimic many of the in vivo actions of mGluR2/3 agonists that may predict therapeutic utility of these compounds.
Footnotes
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This work was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health. Vanderbilt is a site in the National Institutes of Health-supported Molecular Libraries Screening Centers Network.
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R.G. and C.K.J. contributed equally to this work.
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A portion of these studies was presented at the 5th International Meeting on Metabotropic Glutamate Receptors; 2005 September 18-23; Taormina, Italy.
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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.106.102046.
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ABBREVIATIONS: mGluR, metabotropic glutamate receptor; LY379268, (-)-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY354740, (1S,2S,5R,6S)-2-oxabicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate; LY487379, N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine; BINA, biphenyl-indanone A, 3′-[[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl]biphenyl-4-carboxylic acid; 2, 2′-cyclopentyl-2,3-dimethyl-4-methoxyacetophenone, cyclopentylacetophenone; 3, 1-(4-methoxy-2,3-dimethylphenyl)-2-cyclopentyl-2-propenone; 4, 2-cyclopentyl-5-methoxy-6,7-dimethylindan-1-one, methoxyinandone; 5, 2-cyclopentyl-5-hydroxy-6,7-dimethylindan-1-one, indanol; 8, ethyl 3′-methylbiphenyl-4-carboxylate, biphenyl; THF, tetrahydrofuran; 9, ethyl 3′-bromomethylbiphenyl-4-carboxylate; 10, ethyl 3′-(((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)methyl)biphenyl-4-carboxylate; r, rat; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; HEK, human embryonic kidney; CHO, Chinese hamster ovary; h, human; GTPγS, guanosine 5′-[γ-thio]triphosphate; l-AP4, l-(+)-2-amino-4-phosphonobutyric acid; DMSO, dimethyl sulfoxide; ACSF, artificial cerebrospinal fluid; MPP, medial perforant path; fEPSP, field excitatory postsynaptic potentials; DCG-IV, (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine; PCP, phencyclidine; PPI, prepulse inhibition; LY341495, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; ANOVA, analysis of variance; DG, dentate gyrus.
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↵1 Current affiliation: Johnson and Johnson, San Diego, CA.
- Received January 30, 2006.
- Accepted March 24, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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Biphenyl-indanone A, a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor Subtype 2, Has Antipsychotic- and Anxiolytic-Like Effects in Mice
