title: A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo.
abstract: Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to mGluR8) act as important pre- and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTPgammaS binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those of L-2-amino-4-phosphonobutyrate (L-AP4) and superior to those of L-glutamate. AMN082 (< or = 10 microM) failed to show appreciable activating or inhibitory effects at other mGluR subtypes and selected ionotropic GluRs. Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands. Here we provide evidence for full agonist activity mediated by the heptahelical domain of family 3 G protein-coupled receptors (which have mGluR-like structure) that may lead to drug development opportunities. Further, AMN082 is orally active, penetrates the blood-brain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion. Therefore, AMN082 is a valuable tool for unraveling the role of mGluR7 in stress-related CNS disorders.
authors.affiliation: Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Kayo
authors.initials: K
authors.lastname: Mitsukawa
authors.forename: Rina
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Silvio
authors.initials: S
authors.lastname: Ofner
authors.forename: Joachim
authors.initials: J
authors.lastname: Nozulak
authors.forename: Oliver
authors.initials: O
authors.lastname: Pescott
authors.forename: Snezana
authors.initials: S
authors.lastname: Lukic
authors.forename: Natacha
authors.initials: N
authors.lastname: Stoehr
authors.forename: Cedric
authors.initials: C
authors.lastname: Mombereau
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuhn
authors.forename: Kevin H
authors.initials: KH
authors.lastname: McAllister
authors.forename: Herman
authors.initials: H
authors.lastname: van der Putten
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flor
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D006728:Hormones / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological / Q000503:physiopathology*
chemical_list: D001559:Benzhydryl Compounds; D006728:Hormones; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7