QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.061747v1 309/2/568    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O'Brien, J. A. Articles by Williams, D. L. Search for Related Content PubMed PubMed Citation Articles by O'Brien, J. A. Articles by Williams, D. L., Jr.

NEUROPHARMACOLOGY

A Novel Selective Allosteric Modulator Potentiates the Activity of Native Metabotropic Glutamate Receptor Subtype 5 in Rat Forebrain

Neuroscience-WP, Merck Research Laboratories, West Point, Pennsylvania (J.A.O., W.L., M.W., M.A.J., C.S., D.J.P., D.L.W.); Molecular Systems, Merck Research Laboratories, Rahway, New Jersey (S.N.H.); Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania (D.D.W., C.W.L., M.E.D.); Neurobiology, Merck Research Laboratories, San Diego, California (H.J.S.); Molecular Neuroscience, Merck Research Laboratories, San Diego, California (B.R.); and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (P.J.C.)

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- to 8-fold with EC₅₀ values in the 400 to 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 although DFB partially competed for [³H]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 µM) potentiated NMDA receptor currents in hippocampal slices induced by threshold levels of DHPG, whereas having no effect on these currents by itself. Similarly, 10 µM 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.

Address correspondence to: Dr. David L. Williams, Jr., WP46-300, Merck Research Laboratories, West Point, PA 19486. E-mail: david_williams1{at}merck.com

This article has been cited by other articles:

				Y. Chen, C. Goudet, J.-P. Pin, and P. J. Conn N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) Acts through a Novel Site as a Positive Allosteric Modulator of Group 1 Metabotropic Glutamate Receptors Mol. Pharmacol., March 1, 2008; 73(3): 909 - 918. [Abstract] [Full Text] [PDF]

				G. Suzuki, N. Tsukamoto, H. Fushiki, A. Kawagishi, M. Nakamura, H. Kurihara, M. Mitsuya, M. Ohkubo, and H. Ohta In Vitro Pharmacological Characterization of Novel Isoxazolopyridone Derivatives as Allosteric Metabotropic Glutamate Receptor 7 Antagonists J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 147 - 156. [Abstract] [Full Text] [PDF]

				C. J. Langmead Screening for Positive Allosteric Modulators: Assessment of Modulator Concentration-Response Curves as a Screening Paradigm J Biomol Screen, August 1, 2007; 12(5): 668 - 676. [Abstract] [PDF]

				K. Hemstapat, H. Da Costa, Y. Nong, A. E. Brady, Q. Luo, C. M. Niswender, G. D. Tamagnan, and P. J. Conn A Novel Family of Potent Negative Allosteric Modulators of Group II Metabotropic Glutamate Receptors J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 254 - 264. [Abstract] [Full Text] [PDF]

				G. Suzuki, T. Kimura, A. Satow, N. Kaneko, J. Fukuda, H. Hikichi, N. Sakai, S. Maehara, H. Kawagoe-Takaki, M. Hata, et al. Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC) J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1144 - 1153. [Abstract] [Full Text] [PDF]

				Y. Chen, Y. Nong, C. Goudet, K. Hemstapat, T. de Paulis, J.-P. Pin, and P. J. Conn Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses Mol. Pharmacol., May 1, 2007; 71(5): 1389 - 1398. [Abstract] [Full Text] [PDF]

				P. Rondard, J. Liu, S. Huang, F. Malhaire, C. Vol, A. Pinault, G. Labesse, and J.-P. Pin Coupling of Agonist Binding to Effector Domain Activation in Metabotropic Glutamate-like Receptors J. Biol. Chem., August 25, 2006; 281(34): 24653 - 24661. [Abstract] [Full Text] [PDF]

				K. Hemstapat, T. de Paulis, Y. Chen, A. E. Brady, V. K. Grover, D. Alagille, G. D. Tamagnan, and P. J. Conn A Novel Class of Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Interact with a Site Distinct from That of Negative Allosteric Modulators Mol. Pharmacol., August 1, 2006; 70(2): 616 - 626. [Abstract] [Full Text] [PDF]

				Y. Zhang, A. L. Rodriguez, and P. J. Conn Allosteric Potentiators of Metabotropic Glutamate Receptor Subtype 5 Have Differential Effects on Different Signaling Pathways in Cortical Astrocytes J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1212 - 1219. [Abstract] [Full Text] [PDF]

				A. L. Rodriguez, Y. Nong, N. K. Sekaran, D. Alagille, G. D. Tamagnan, and P. J. Conn A Close Structural Analog of 2-Methyl-6-(phenylethynyl)-pyridine Acts as a Neutral Allosteric Site Ligand on Metabotropic Glutamate Receptor Subtype 5 and Blocks the Effects of Multiple Allosteric Modulators Mol. Pharmacol., December 1, 2005; 68(6): 1793 - 1802. [Abstract] [Full Text] [PDF]

				G. G. Kinney, J. A. O'Brien, W. Lemaire, M. Burno, D. J. Bickel, M. K. Clements, T.-B. Chen, D. D. Wisnoski, C. W. Lindsley, P. R. Tiller, et al. A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 199 - 206. [Abstract] [Full Text] [PDF]