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Received for publication October 17, 2003.
Revised January 12, 2004.
Accepted for publication January 26, 2004.
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 Ca2+ assays 7-8 fold with EC50 values in the 400-800 nM range, and at 10 µM 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 [3H]-quisqualate binding to mGluR5, but while DFB partially competed for [3H]-methoxyPEPy binding, CPPHA had no effect on the binding of this MPEP analogue to mGluR5. Although the binding sites for the two classes of allosteric modulators appear 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 NMDA receptor currents in the CA1 region of hippocampal slices. We found that CPPHA (10 µM) potentiated NMDA receptor currents in hippocampal slices induced by threshold levels of DHPG, while having no effect on these currents by itself. Similarly, 10 µM CPPHA also potentiated mGluR5-mediated DHPG-induced depolarization of rat STN neurons. These results demonstrate that allosteric potentiation of mGluR5 increases the effect of threshold agonist concentrations in native systems.
Key words:
allosteric, electrophysiology, glutamate, mGluR5, metabotropic, potentiator
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