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A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain.
| Content Provider | Semantic Scholar |
|---|---|
| Author | O'brien, Julie A. Lemaire, Wei Wittmann, Marion Jacobson, Marlene A. Ha, Sookhee Wisnoski, David D. Lindsley, Craig W. Schaffhauser, Hervé J. Rowe, Blake Sur, Cyrille Duggan, Mark E. Pettibone, Douglas J. Conn, P. Jeffrey Williams, David L. |
| Copyright Year | 2004 |
| Abstract | We found that N-[4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl]-2-hydroxybenzamide (CPPHA), is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). CPPHA alone had no agonist activity and acted as a selective positive allosteric modulator of human and rat mGluR5. CPPHA potentiated threshold responses to glutamate in fluorometric Ca(2+) assays 7- to 8-fold with EC(50) values in the 400 to 800 nM range, and at 10 microM shifted mGluR5 agonist concentration-response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine (DHPG) 4- to 7-fold to the left. The only effect of CPPHA on other mGluRs was weak inhibition of mGluR4 and 8. Neither CPPHA nor the previously described 3,3'-difluorobenzaldazine (DFB) affected [(3)H]quisqualate binding to mGluR5, but although DFB partially competed for [(3)H]3-methoxy-5-(2-pyridinylethynyl)pyridine binding, CPPHA had no effect on the binding of this 2-methyl-6-(phenylethynyl)-pyridine analog to mGluR5. Although the binding sites for the two classes of allosteric modulators seem to be different, these different allosteric sites can modulate functionally and mechanistically similar allosteric effects. In electrophysiological studies of brain slice preparations, it had been previously shown that activation of mGluR5 receptors by agonists increased N-methyl-D-aspartate (NMDA) receptor currents in the CA1 region of hippocampal slices. We found that CPPHA (10 microM) potentiated NMDA receptor currents in hippocampal slices induced by threshold levels of DHPG, whereas having no effect on these currents by itself. Similarly, 10 microM CPPHA also potentiated mGluR5-mediated DHPG-induced depolarization of rat subthalamic nucleus neurons. These results demonstrate that allosteric potentiation of mGluR5 increases the effect of threshold agonist concentrations in native systems. |
| Starting Page | 3 |
| Ending Page | 5 |
| Page Count | 3 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://jpet.aspetjournals.org/content/jpet/309/2/568.full.pdf |
| Alternate Webpage(s) | http://www.mc.vanderbilt.edu/labs/lindsley/pdfs/pdfs_From_Publication_List/J%20Pharm%20Exp%20Ther%20(2004)_Vol%20309(2)_568-577.pdf |
| PubMed reference number | 14747613v1 |
| Volume Number | 309 |
| Issue Number | 2 |
| Journal | The Journal of pharmacology and experimental therapeutics |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 3,3'-difluorobenzaldazine Analog Aspartic Acid Binding Sites CA1 field Cell Nucleus Class Ganciclovir Glutamate Receptor Glutamic Acid Hippocampus (Brain) Modulator Device Component N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Parathyroid Hormone Receptor Prosencephalon Quisqualate Receptors, Metabotropic Glutamate Structure of subthalamic nucleus chemosensitization/potentiation |
| Content Type | Text |
| Resource Type | Article |
