MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on April 27, 2006; DOI: 10.1124/mol.105.021857

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.105.021857v1
70/2/616    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by hemstapat, K.
Right arrow Articles by Conn, P J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by hemstapat, K.
Right arrow Articles by Conn, P J.


Received for publication December 23, 2005.
Revised April 6, 2006.
Accepted for publication April 27, 2006.

A NOVEL CLASS OF POSITIVE ALLOSTERIC MODULATORS OF mGluR1 INTERACT WITH A SITE DISTINCT FROM THAT OF NEGATIVE ALLOSTERIC MODULATORS

Kamondanai hemstapat 1, Tomas de Paulis 1, Yelin Chen 1, Ashley E Brady 1, Vandana K Grover 1, David Alagille 2, Gilles D Tamagnan 2, P Jeffrey Conn 1*

1 Vanderbilt university Medical Center 2 Institute for Neurodegenerative Disorders

* Address correspondence to: E-mail: jeff.conn{at}vanderbilt.edu

Abstract

We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), that act as positive allosteric modulators (potentiators) of metabotropic glutamate receptor subtype 5 (mGluR5). Studies of CDPPB analogs revealed that some compounds in this series serve also as positive allosteric modulators of mGluR1. Although CDPPB is selective for mGluR5 relative to other mGluR subtypes, several CDPPB analogs also showed 2.5-fold potentiation of glutamate-induced calcium transients in cells expressing mGluR1 at 10 µM, with N-(1,3-diphenyl-1H-pyrazol-4-yl)benzamide (VU-64) being selective for mGluR1. In previous studies, we found that two structural classes of mGluR5-selective allosteric potentiators, including CDPPB, share a common binding site with the allosteric mGluR5 antagonist MPEP. Negative allosteric modulators of mGluR1, regardless of structural class, have been reported to bind to a common allosteric antagonist site on this receptor. However, neither the novel CDPPB analogs, nor previously identified allosteric mGluR1 potentiators, e.g. Ro 67-7476, Ro 01-6128 and Ro 67-4853, displaced the binding of [3H]R214127, a high-affinity radioligand for the allosteric antagonist site on mGluR1 at concentrations several orders of magnitude higher than those required to induce allosteric potentiation of mGluR1 responses. These data suggest that allosteric potentiators of mGluR1 act at a site that is distinct from that of allosteric antagonists of mGluR1. Site-directed mutagenesis revealed that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGluR1 potentiators.


Key words: Metabotropic glutamate, Gi family, Gq/11 family, Fluorescence techniques, Mutagenesis/Chimeric approaches, Receptor-mediated


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 Mol. Pharmacol.Home page
T. Lee, R. Schwandner, G. Swaminath, J. Weiszmann, M. Cardozo, J. Greenberg, P. Jaeckel, H. Ge, Y. Wang, X. Jiao, et al.
Identification and Functional Characterization of Allosteric Agonists for the G Protein-Coupled Receptor FFA2
Mol. Pharmacol., December 1, 2008; 74(6): 1599 - 1609.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
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]

Home page
 Mol. Pharmacol.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 Mol. Pharmacol.Home page
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]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics