![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 59, Issue 5, 965-973, May 2001
Institut National de la Santé et de la Recherche
Médicale-Centre National de la Recherche Scientifique de
Pharmacologie-Endocrinologie-UPR 9023, Montpellier, France (F.Y.C.,
I.B., C.J., J.B., J.P.P., L.P.); Bayer AG, PharmaResearch, Wuppertal,
Germany (A.S., A.V., F.M., H.A., T.M.); and Department of Pharmacology,
Monash University, Victoria, Australia (P.M.B.)
L-Glutamate (Glu) activates at least eight different G
protein-coupled receptors known as metabotropic glutamate (mGlu)
receptors, which mostly act as regulators of synaptic transmission.
These receptors consist of two domains: an extracellular domain in
which agonists bind and a transmembrane heptahelix region involved in G
protein activation. Although new mGlu receptor agonists and antagonists
have been described, few are selective for a single mGlu subtype. Here,
we have examined the effects of a novel compound, BAY36-7620
[(3aS,6aS)- 6a-Naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on], on mGlu receptors (mGlu1-8), transiently expressed in human embryonic kidney 293 cells. BAY36-7620 is a potent (IC50 = 0.16 µM) and selective antagonist at mGlu1 receptors and inhibits >60%
of mGlu1a receptor constitutive activity (IC50 = 0.38 µM). BAY36-7620 is therefore the first described mGlu1 receptor
inverse agonist. To address the mechanism of action of BAY36-7620, Glu
dose-response curves were performed in the presence of increasing
concentrations of BAY36-7620. The results show that BAY36-7620 largely
decreases the maximal effect of Glu. Moreover, BAY36-7620 did not
displace the [3H]quisqualate binding from the Glu-binding
pocket, further indicating that BAY36-7620 is a noncompetitive mGlu1
antagonist. Studies of chimeric receptors containing regions of mGlu1
and regions of DmGluA, mGlu2, or mGlu5, revealed that the transmembrane
region of mGlu1 is necessary for activity of BAY36-7620. Transmembrane helices 4 to 7 are shown to play a critical role in the selectivity of
BAY36-7620. This specific site of action of BAY36-7620 differs from
that of competitive antagonists and indicates that the transmembrane region plays a pivotal role in the agonist-independent activity of this
receptor. BAY36-7620 will be useful to further delineate the functional
importance of the mGlu1 receptor, including its putative
agonist-independent activity.
This article has been cited by other articles:
|
|
 |
|
  C. Gil-Sanz, J. M. Delgado-Garcia, A. Fairen, and A. Gruart Involvement of the mGluR1 Receptor in Hippocampal Synaptic Plasticity and Associative Learning in Behaving Mice Cereb Cortex, July 1, 2008; 18(7): 1653 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. M. Stropes and W. E. Miller Functional analysis of human cytomegalovirus pUS28 mutants in infected cells J. Gen. Virol., January 1, 2008; 89(1): 97 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nakamoto, V. Nalavadi, M. P. Epstein, U. Narayanan, G. J. Bassell, and S. T. Warren Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors PNAS, September 25, 2007; 104(39): 15537 - 15542. [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]
|
|
|
|
 |
|
 J. Namkoong, S.-S. Shin, H. J. Lee, Y. E. Marin, B. A. Wall, J. S. Goydos, and S. Chen Metabotropic Glutamate Receptor 1 and Glutamate Signaling in Human Melanoma Cancer Res., March 1, 2007; 67(5): 2298 - 2305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Mathiesen, A. Christopoulos, T. Ulven, J. F. Royer, M. Campillo, A. Heinemann, L. Pardo, and E. Kostenis On the Mechanism of Interaction of Potent Surmountable and Insurmountable Antagonists with the Prostaglandin D2 Receptor CRTH2 Mol. Pharmacol., April 1, 2006; 69(4): 1441 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kohara, T. Toya, S. Tamura, T. Watabiki, Y. Nagakura, Y. Shitaka, S. Hayashibe, S. Kawabata, and M. Okada Radioligand Binding Properties and Pharmacological Characterization of 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a High-Affinity, Selective, and Noncompetitive Antagonist of Metabotropic Glutamate Receptor Type 1 J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 163 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Binet, C. Brajon, L. Le Corre, F. Acher, J.-P. Pin, and L. Prezeau The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor J. Biol. Chem., July 9, 2004; 279(28): 29085 - 29091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Bettler, K. Kaupmann, J. Mosbacher, and M. Gassmann Molecular Structure and Physiological Functions of GABAB Receptors Physiol Rev, July 1, 2004; 84(3): 835 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Goudet, F. Gaven, J. Kniazeff, C. Vol, J. Liu, M. Cohen-Gonsaud, F. Acher, L. Prezeau, and J. P. Pin Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors PNAS, January 6, 2004; 101(1): 378 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kenakin Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism Mol. Pharmacol., January 1, 2004; 65(1): 2 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. O'Brien, W. Lemaire, T.-B. Chen, R. S. L. Chang, M. A. Jacobson, S. N. Ha, C. W. Lindsley, H. J. Schaffhauser, C. Sur, D. J. Pettibone, et al. A Family of Highly Selective Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 Mol. Pharmacol., September 1, 2003; 64(3): 731 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lavreysen, C. Janssen, F. Bischoff, X. Langlois, J. E. Leysen, and A. S. J. Lesage [3H]R214127: A Novel High-Affinity Radioligand for the mGlu1 Receptor Reveals a Common Binding Site Shared by Multiple Allosteric Antagonists Mol. Pharmacol., May 1, 2003; 63(5): 1082 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Malherbe, N. Kratochwil, F. Knoflach, M.-T. Zenner, J. N. C. Kew, C. Kratzeisen, H. P. Maerki, G. Adam, and V. Mutel Mutational Analysis and Molecular Modeling of the Allosteric Binding Site of a Novel, Selective, Noncompetitive Antagonist of the Metabotropic Glutamate 1 Receptor J. Biol. Chem., February 28, 2003; 278(10): 8340 - 8347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Christopoulos and T. Kenakin G Protein-Coupled Receptor Allosterism and Complexing Pharmacol. Rev., June 1, 2002; 54(2): 323 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lavreysen, E. Le Poul, P. Van Gompel, L. Dillen, J. E. Leysen, and A. S. J. Lesage Supersensitivity of Human Metabotropic Glutamate 1a Receptor Signaling in L929sA Cells Mol. Pharmacol., May 1, 2002; 61(5): 1244 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Perroy, G. J. Gutierrez, V. Coulon, J. Bockaert, J.-P. Pin, and L. Fagni The C Terminus of the Metabotropic Glutamate Receptor Subtypes 2 and 7 Specifies the Receptor Signaling Pathways J. Biol. Chem., November 30, 2001; 276(49): 45800 - 45805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Pin, M.-L. Parmentier, and L. Prezeau Positive Allosteric Modulators for gamma -Aminobutyric AcidB Receptors Open New Routes for the Development of Drugs Targeting Family 3 G-Protein-Coupled Receptors Mol. Pharmacol., November 1, 2001; 60(5): 881 - 884. [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
