Gee, Christine, Peterlik, Daniel, Neuhäuser, Christoph, Bouhelal, Rochdi, Kaupmann, Klemens, Laue, Grit, Uschold-Schmidt, Nicole, Feuerbach, Dominik, Zimmermann, Kaspar, Ofner, Silvio, Cryan, John F., Van Der Putten, P. Herman, Fendt, Markus, Vranesic, Ivan-Toma, Glatthar, Ralf and Flor, Peter Josef (2014) Inhibition of Amygdala Plasticity, Stress and Anxiety Behavior by Blocking at the Venus Flytrap Domain (VFTD) of the Metabotropic Glutamate Receptor Subtype 7 (mGlu7). Journal of Biological Chemistry, 289 (16). pp. 10975-10987. ISSN ISSN:0021-9258

Abstract

The metabotropic glutamate receptor subtype 7 (mGlu7) acts as important presynaptic regulator of neurotransmission in the mammalian CNS and has been linked, via the use of behavioral genetics and pharmacology, to various psychiatric conditions including 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 XAP044 [7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one] which inhibits lateral amygdala long-term potentiation (LTP) in slices from wildtype mice with a half-maximal blockade at 88 nM. There was no effect of XAP044 on this LTP of mGlu7-deficient mice indicating that the effect was due to mGlu7 antagonism. Unexpectedly and in contrast to all previous mGlu7-selective ligands, XAP044 binds to a novel molecular pocket that localizes in mGlu7’s extracellular Venus flytrap domain (VFTD), which is generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. In rodent behavioral analysis, XAP044 demonstrates wide-spectrum antistress, antidepressant-like, and anxiolytic efficacy, including less freezing during acquisition of Pavlovian fear and reduced innate anxiety, which is well consistent with the phenotypes of mGlu7-deficient mice, mGlu7 siRNA knockdown studies and with our amygdala LTP effects of XAP044. Taken together, we here provide a novel molecular mode of pharmacological action with significant application potential in psychiatry, i.e. blocking mGlu7 signaling via its VFTD, who’s high-resolution 3D-structure is known, which may facilitate future drug development via the use of computer-assisted drug design.

Item Type:	Article
Keywords:	Stress, Receptors, Pharmacology, Glutamate, Neurotransmitter Release, Anxiety, Amygdala Plasticity, XAP044, mGlu7, Metabotropic Glutamate Receptor
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/20021