Abstract
Group II metabotropic glutamate receptors (mGluRs), mGluR2 and mGluR3, play a number of important roles in mammalian brain and represent exciting new targets for certain central nervous system disorders. We now report synthesis and characterization of a novel family of derivatives of dihydrobenzo[1,4]diazepin-2-one that are selective negative allosteric modulators for group II mGluRs. These compounds inhibit both mGluR2 and mGluR3 but have no activity at group I and III mGluRs. The novel mGluR2/3 antagonists also potently block mGluR2/3-mediated inhibition of the field excitatory postsynaptic potentials at the perforant path synapse in hippocampal slices. These compounds induce a rightward shift and decrease the maximal response in the glutamate concentration-response relationship, consistent with a noncompetitive antagonist mechanism of action. Furthermore, radioligand binding studies revealed no effect on binding of the orthosteric antagonist [3H]LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionic acid]. Site-directed mutagenesis revealed that a single point mutation in transmembrane V (N735D), previously shown to be an important residue for potentiation activity of the mGluR2 allosteric potentiator LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], is not critical for the inhibitory activity of negative allosteric modulators of group II mGluRs. However, this single mutation in human GluR2 almost completely blocked the enhancing activity of biphenyl-indanone A, a novel allosteric potentiator of mGluR2. Our data suggest that these two positive allosteric modulators of mGluR2 may share a common binding site and that this site may be distinct from the binding site for the new negative allosteric modulators of group II mGluRs.
Footnotes
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This work was supported by grants from National Institute of Mental Health; NINDS, National Institutes of Health; The National Alliance for Research on Schizophrenia and Depression; and the Stanley Foundation. Vanderbilt University is a site in the National Institutes of Health-supported Molecular Libraries Screening Center Network.
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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.106.117093.
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ABBREVIATIONS: mGluR, metabotropic glutamate receptor; CHO, Chinese hamster ovary; HEK, human embryonic kidney; TM, transmembrane; DCG-IV, (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine; LY341495, 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionic acid; LY487379, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroetylsulfonyl)-pyrid-3-ylmethylamine; BINA, biphenyl-indanone A or 3′-(((2-cyclopropyl-6,7-dimethl-1-oxo2,3-dihydro-1H-inden-5-yl)oxy)methyl)biphenyl-4-carboxylic acid; DMSO, dimethyl sulfoxide; [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; ACSF, artificial cerebrospinal fluid; l-AP4, L(+)-2-amino-4-phosphonobutyric acid; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; MPP, medial perforant path; fEPSP, field excitatory postsynaptic potential; LY379268, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate; LY354740, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; MGS0039, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; MNI-135, 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile; MNI-136, 7-bromo-4-(3-pyridin-3-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one; MNI-137, 4-(7-bromo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile; HBSS, Hanks' balanced salt solution; DG, dentate granule; hmGluR, human GluR; rmGluR, rat GluR.
- Received November 14, 2006.
- Accepted April 5, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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A Novel Family of Potent Negative Allosteric Modulators of Group II Metabotropic Glutamate Receptors
