BAY36-7620: A Potent Non-Competitive mGlu1 Receptor Antagonist with Inverse Agonist Activity.

Carroll, Fiona Y.; Stolle, A.; Beart, Philip M; Voerste, Arnd; Brabet, Isabelle; Mauler, Frank; Joly, Cécile; Antonicek, Horst; Bockaert, Joël; Müller, Thomas; Pin, Jean‐Philippe; Prézeau, Laurent

doi:10.1124/mol.59.5.965

Cited by 164 publications

(136 citation statements)

References 32 publications

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“…Firstly, several non-competitive antagonists that have been identified in pharmaceutical industries and found to interact in the HD of these receptors, act as inverse agonists, probably by directly stabilizing the inactive state of the HD. This is the case for the mGlu1 selective antagonist BAY36-7620 ((3aS,6aS)-6a-Naphtalen-2-ylmethyl-5-methylidenhexahydro-cyclopental[c]furan-1-on) (Carroll et al, 2001), and for the mGlu5 selective antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) (Pagano et al, 2000). Secondly, if the HD is really at the origin of the constitutive activity of these receptors, such activity may also be measurable with the a receptor truncated of the large ECD.…”

Section: The Heptahelical Domain Of Group-i Mglurs Displays Constitutmentioning

confidence: 99%

The activation mechanism of class-C G-protein coupled receptors

Kniazeff

Goudet

et al. 2004

Biology of the Cell

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, either homo or heterodimers. This complex architecture raises a number of important questions. Here we will discuss our view of how agonist binding within the large ECD triggers the necessary change of conformation, or stabilize a specific conformation, of the heptahelical domain leading to G-protein activation. How ligands acting within the heptahelical domain can change the properties of these complex macromolecules.

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Section: The Heptahelical Domain Of Group-i Mglurs Displays Constitutmentioning

confidence: 99%

The activation mechanism of class-C G-protein coupled receptors

Kniazeff

Goudet

et al. 2004

Biology of the Cell

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“…Such compounds act either as non-competitive antagonists (32)(33)(34) or as positive allosteric modulators (35)(36)(37)(38)(39)(40). In each case, these compounds have been shown to bind within the HD of their targeted receptor (34,(41)(42)(43).…”

mentioning

confidence: 99%

The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor

Binet

Brajon

Corre

et al. 2004

Journal of Biological Chemistry

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The ␥-aminobutyric acid, type B (GABA B ) receptor is well recognized as being composed of two subunits, GABA B1 and GABA B2 . Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA B1 binds GABA, GABA B2 is required for GABA B1 to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA B2 plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA B2 can transmit a signal in the absence of GABA B1 . Today only ligands interacting with GABA B1 ECD have been identified. Thus, the compounds acting exclusively on the GABA B2 subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA B receptor. We showed that it activates the wild type GABA B receptor but with a low efficacy. The GABA B2 HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA B1 . Of interest, CGP7930 could activate GABA B2 expressed alone and is the first described agonist of GABA B2 . Finally, we show that CGP7930 retains its agonist activity on a GABA B2 subunit deleted of its ECD. This demonstrates that the HD of GABA B2 behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA B receptor and examine any possible role of homomeric GABA B2 receptors.

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“…This process results in receptor activation (Costantino et al 1999;Rondard and Pin 2015;Takahashi et al 1993). The other binding site, for positive and negative allosteric modulators, is located within the 7TM domain (Carroll et al 2001;Gregory and Conn 2015;Litschig et al 1999). Binding of a negative allosteric modulator to this site results in non-competitive inhibition of the receptor.…”

Section: Pharmacologymentioning

confidence: 99%

Control of neuronal excitability by Group I metabotropic glutamate receptors

Amb

Jds

et al. 2017

Biophys Rev

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Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu 1 and mGlu 5 . Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gα q , which can activate PLCβ, leading initially to the formation of IP 3 and diacylglycerol. IP 3 can release Ca 2+ from cellular stores resulting in activation of Ca 2+ -dependent ion channels. Intracellular Ca 2+ , together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

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BAY36-7620: A Potent Non-Competitive mGlu1 Receptor Antagonist with Inverse Agonist Activity.

Cited by 164 publications

References 32 publications

The activation mechanism of class-C G-protein coupled receptors

The activation mechanism of class-C G-protein coupled receptors

The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor

Control of neuronal excitability by Group I metabotropic glutamate receptors

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