作者: Cristiano, Nunzia ; Brabet, Isabelle ; Tora, Amelie ; Goupil-Lamy, Anne ; Flor, Peter J. ; Pin, Jean-Philippe ; Goudet, Cyril ; Glatthar, Ralf ; Acher, Francine C. ; Bertrand, Hugues-Olivier ; McCort-Tranchepain, Isabelle ; Cabayé, Alexandre

Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

2018-03-01·Neuropharmacology

Role of mGlu7 receptor in morphine rewarding effects is uncovered by a novel orthosteric agonist

Article

作者: Florence Noble ; Francine Acher ; Corinne Canestrelli ; Zuzana Hajasova ; Nicolas Marie

Opiate dependence is a major health issue and despite the existence of opioid substitution treatment, relapse frequently occurs. Group III metabotropic glutamate (mGlu) receptors has received much attention as a putative target in ethanol and cocaine addiction, but no data on opiate addiction exist. So we investigated the role of group III mGlu receptors in morphine rewarding effects through the expression and the reinstatement of conditioned place preference (CPP) using a newly synthesized mGlu4/mGlu7 receptor orthosteric agonist, LSP2-9166. We found that LSP2-9166 blocked morphine CPP expression and reinstatement after extinction. Blockade of CPP expression with LSP2-9166 was abolished when using XAP044, a mGlu7 antagonist. We also found that LSP2-9166 at the dose active for blocking morphine reward was devoid of any effect on locomotion, hedonic state, spatial memory, anxiety or depression. Altogether our data demonstrated that group III mGlu receptors, and more specifically mGlu7, might be a valuable target in opiate addiction.

2014-04-01·Journal of Biological Chemistry2区 · 生物学

Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

2区 · 生物学

Article

作者: Peter J. Flor ; Dominik Feuerbach ; Christine E. Gee ; Ivo Vranesic ; Rochdi Bouhelal ; Ralf Glatthar ; Nicole Uschold-Schmidt ; Kaspar Zimmermann ; Grit Laue ; Daniel Peterlik ; Klemens Kaupmann ; Silvio Ofner ; Christoph Neuhäuser ; John F. Cryan ; Markus Fendt ; Herman van der Putten

The metabotropic glutamate receptor subtype 7 (mGlu7) is an important presynaptic regulator of neurotransmission in the mammalian CNS. mGlu7 function has been linked to autism, drug abuse, anxiety, and depression. Despite this, it has been difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as amygdala and limbic cortex. Here, we present the mGlu7-selective antagonist 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), which inhibits lateral amygdala long term potentiation (LTP) in brain slices from wild type mice with a half-maximal blockade at 88 nm. There was no effect of XAP044 on LTP of mGlu7-deficient mice, indicating that this pharmacological effect is mGlu7-dependent. Unexpectedly and in contrast to all previous mGlu7-selective drugs, XAP044 does not act via the seven-transmembrane region but rather via a binding pocket localized in mGlu7's extracellular Venus flytrap domain, a region generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. XAP044 demonstrates good brain exposure and wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy in rodent behavioral paradigms. XAP044 reduces freezing during acquisition of Pavlovian fear and reduces innate anxiety, which is consistent with the phenotypes of mGlu7-deficient mice, the results of mGlu7 siRNA knockdown studies, and the inhibition of amygdala LTP by XAP044. Thus, we present an mGlu7 antagonist with a novel molecular mode of pharmacological action, providing significant application potential in psychiatry. Modeling the selective interaction between XAP044 and mGlu7's Venus flytrap domain, whose three-dimensional structure is already known, will facilitate future drug development supported by computer-assisted drug design.

100 项与 XAP-044 相关的药物交易

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