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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.079244v1 313/1/199    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 Citation Map 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 Kinney, G. G. Articles by Williams, D. L. Search for Related Content PubMed PubMed Citation Articles by Kinney, G. G. Articles by Williams, D. L., Jr.

NEUROPHARMACOLOGY

A Novel Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Has in Vivo Activity and Antipsychotic-Like Effects in Rat Behavioral Models

Neuroscience-West Point (G.G.K., J.A.O., W.L., M.B., D.J.B., M.K.C., T.-B.C., M.A.J., C.S., D.L.W.), Medicinal Chemistry (D.D.W., C.W.L., M.E.D.), Drug Metabolism-WP (P.R.T., S.S.), and Neuroscience Drug Discovery (D.J.P.), Merck Research Laboratories, West Point, Pennsylvania; and Pharmacology (P.J.C.), Vanderbilt University Medical Center, Nashville, Tennessee

We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to glutamate in fluorometric Ca²⁺ assays more than 7-fold with an EC₅₀ value of approximately 27 nM. At 1 µM, CDPPB shifted mGluR5 agonist concentration response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine 3- to 9-fold to the left. At higher concentrations, CDPPB exhibited agonist-like activity on cells expressing mGluR5. No other activity was observed on any other mGluR or cell type at concentrations up to 10 µM. CDPPB had no effect on [³H]quisqualate binding to mGluR5 but did compete for binding of [³H]methoxyPEPy, an analog of the selective mGluR5 negative allosteric modulator MPEP. CDPPB was found to be brain penetrant and reversed amphetamine-induced locomotor activity and amphetamine-induced deficits in prepulse inhibition in rats, two models sensitive to antipsychotic drug treatment. These results demonstrate that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGluR5 activity in vivo. These effects are consistent with the hypothesis that allosteric potentiation of mGluR5 may provide a novel approach for development of antipsychotic agents.

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:

				F. Liu, S. Grauer, C. Kelley, R. Navarra, R. Graf, G. Zhang, P. J. Atkinson, M. Popiolek, C. Wantuch, X. Khawaja, et al. ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 827 - 839. [Abstract] [Full Text] [PDF]

				A. E. Brady, C. K. Jones, T. M. Bridges, J. P. Kennedy, A. D. Thompson, J. U. Heiman, M. L. Breininger, P. R. Gentry, H. Yin, S. B. Jadhav, et al. Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 941 - 953. [Abstract] [Full Text] [PDF]

				C. M. Niswender, K. A. Johnson, C. D. Weaver, C. K. Jones, Z. Xiang, Q. Luo, A. L. Rodriguez, J. E. Marlo, T. de Paulis, A. D. Thompson, et al. Discovery, Characterization, and Antiparkinsonian Effect of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 Mol. Pharmacol., November 1, 2008; 74(5): 1345 - 1358. [Abstract] [Full Text] [PDF]

				A. Satow, S. Maehara, S. Ise, H. Hikichi, M. Fukushima, G. Suzuki, T. Kimura, T. Tanaka, S. Ito, H. Kawamoto, et al. Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide] J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 577 - 586. [Abstract] [Full Text] [PDF]

				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]

				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]

				C. H. Large Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol, May 1, 2007; 21(3): 283 - 301. [Abstract] [PDF]

				J. Cilia, P. Hatcher, C. Reavill, and D. N. C. Jones ({+/-}) Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics J Psychopharmacol, May 1, 2007; 21(3): 302 - 311. [Abstract] [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]

				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]

				R. Galici, C. K. Jones, K. Hemstapat, Y. Nong, N. G. Echemendia, L. C. Williams, T. de Paulis, and P. J. Conn Biphenyl-indanone A, a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor Subtype 2, Has Antipsychotic- and Anxiolytic-Like Effects in Mice J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 173 - 185. [Abstract] [Full Text] [PDF]

				P. J. Conn and C. M. Niswender mGluR7's lucky number PNAS, January 10, 2006; 103(2): 251 - 252. [Full Text] [PDF]

				K. Mitsukawa, R. Yamamoto, S. Ofner, J. Nozulak, O. Pescott, S. Lukic, N. Stoehr, C. Mombereau, R. Kuhn, K. H. McAllister, et al. From The Cover: A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo PNAS, December 20, 2005; 102(51): 18712 - 18717. [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]