title: Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland,; Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, D-20249 Hamburg, Germany.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Gee
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peterlik
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Neuhäuser
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Rochdi
authors.initials: R
authors.lastname: Bouhelal
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Grit
authors.initials: G
authors.lastname: Laue
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Uschold-Schmidt
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Ofner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland,; Department of Anatomy and Neuroscience, University of Cork, Cork, Ireland, and.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Herman
authors.initials: H
authors.lastname: van der Putten
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland,; Institute of Pharmacology and Toxicology and Center of Behavioral Brain Sciences, University of Magdeburg, D-39120 Magdeburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland.
authors.forename: Ivo
authors.initials: I
authors.lastname: Vranesic
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland,. Electronic address: ralf.glatthar@novartis.com.
authors.forename: Ralf
authors.initials: R
authors.lastname: Glatthar
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis AG, CH-4057 Basel, Switzerland,; Faculty of Biology and Preclinical Medicine, Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany,. Electronic address: peter.flor@biologie.uni-regensburg.de.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flor
mesh_terms: D000679:Amygdala / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007739:L Cells; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D017434:Protein Structure, Tertiary; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7
keywords: Elevated Plus-Maze; Fear Conditioning; Glutamate Receptors Metabotropic; Neurotransmitter Release; Pharmacology; Stress; Synaptic Plasticity; XAP044