title: A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors.
abstract: Group II metabotropic glutamate receptors (mGluRs), mGluR2 and mGluR3, play a number of important roles in mammalian brain and represent exciting new targets for certain central nervous system disorders. We now report synthesis and characterization of a novel family of derivatives of dihydrobenzo[1,4]diazepin-2-one that are selective negative allosteric modulators for group II mGluRs. These compounds inhibit both mGluR2 and mGluR3 but have no activity at group I and III mGluRs. The novel mGluR2/3 antagonists also potently block mGluR2/3-mediated inhibition of the field excitatory postsynaptic potentials at the perforant path synapse in hippocampal slices. These compounds induce a rightward shift and decrease the maximal response in the glutamate concentration-response relationship, consistent with a noncompetitive antagonist mechanism of action. Furthermore, radioligand binding studies revealed no effect on binding of the orthosteric antagonist [(3)H]LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionic acid]. Site-directed mutagenesis revealed that a single point mutation in transmembrane V (N735D), previously shown to be an important residue for potentiation activity of the mGluR2 allosteric potentiator LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], is not critical for the inhibitory activity of negative allosteric modulators of group II mGluRs. However, this single mutation in human GluR2 almost completely blocked the enhancing activity of biphenyl-indanone A, a novel allosteric potentiator of mGluR2. Our data suggest that these two positive allosteric modulators of mGluR2 may share a common binding site and that this site may be distinct from the binding site for the new negative allosteric modulators of group II mGluRs.
authors.affiliation: Department of Pharmacology and Vanderbilt Institute of Chemical Biology, Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kamondanai
authors.initials: K
authors.lastname: Hemstapat
authors.forename: Herve
authors.initials: H
authors.lastname: Da Costa
authors.forename: Yi
authors.initials: Y
authors.lastname: Nong
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Brady
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Luo
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Gilles D
authors.initials: GD
authors.lastname: Tamagnan
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000494:Allosteric Regulation; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D014966:Xanthenes / Q000378:metabolism
chemical_list: D000596:Amino Acids; C114624:LY 341495; C476436:N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2