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Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee (Y.C.); Department of Pharmacology and Vanderbilt Institute of Chemical Biology Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee (Y.C., Y.N., K.H., T.D.P., P.J.C.); and Institut de Génomique Fonctionelle, Montpellier, France (C.G., J.-P.P.); Centre National de Recherche Scientifique Unité Mixte de Recherche 5203, Montpellier, France (C.G., J.-P.P.); Institut National de la Santéet de la Recherche Médicale, U661, Montpellier, France (C.G., J.-P.P.); and Université de Montpellier (IFR3), Montpellier, France (C.G., J.-P.P.)

Exciting advances have been made in the discovery of selective positive allosteric modulators of the metabotropic glutamate receptor (mGluR) mGluR5. These compounds may provide a novel approach that could be useful in the treatment of certain central nervous system disorders. However, because of their low potencies, previously described mGluR5 potentiators are not useful for functional studies in native preparations. In addition, binding sites at which these compounds act have not been identified. It has been suggested that two allosteric potentiators, 3,3'-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), act by binding to the same allosteric site as the negative allosteric modulators of mGluR5 such as 2-methyl-6-(phenylethynyl)pyridine (MPEP). However, another mGluR5 potentiator, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)m-ethyl]phenyl}-2-hydroxybenzamide, does not bind to this site, bringing this hypothesis into question. We have synthesized a series of CDPPB analogs and report that these compounds bind to the MPEP site with affinities that are closely related to their potencies as mGluR5 potentiators. Furthermore, allosteric potentiation is antagonized by a neutral ligand at the MPEP site and reduced by a mutation of mGluR5 that eliminates MPEP binding. Together, these data suggest that interaction with the MPEP site is important for allosteric potentiation of mGluR5 by CDPPB and related compounds. In addition, whole-cell patch-clamp studies in midbrain slices reveal that a highly potent analog of CDPPB, 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), selectively potentiates mGluR5 but not mGluR1-mediated responses in midbrain neurons, whereas a previously identified allosteric potentiator of mGluR1 has the opposite effect.

Received for publication November 7, 2006.

Accepted for publication February 13, 2007.

Address correspondence to: Dr. P. Jeffrey Conn, Department of Pharmacology, Vanderbilt University Medical Center, 23rd Avenue South at Pierce, 417-D Preston Research Building, Nashville, TN 37232-6600. E-mail: jeff.conn{at}vanderbilt.edu

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