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 concentrationresponse relationship, consistent with a noncompetitive antagonist mechanism of action. Furthermore, radioligand binding studies revealed no effect on binding of the orthosteric antag-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.The eight known subtypes of metabotropic glutamate receptors (mGluRs) have been classified based on sequence homology, pharmacology, and signal transduction. These include group I (mGluR1 and 5), group II (mGluR2 and 3), and group III receptors (mGluR4, 6, 7, and 8). The group I receptors couple to G ␣q and phospholipase C, whereas group II and group III mGluRs couple to G ␣i (Conn and Pin, 1997;Schoepp et al., 1999). A large body of in vitro and in vivo preclinical studies suggest that specific mGluR subtypes play a broad range of neuromodulatory roles in different central nervous system circuits and that specific subtypes may provide viable targets for novel treatment strategies for a range of neurological and psychiatric disorders, including anxiety (Linden

No abstract

Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl-and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC 50 5 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases. E.C.H. and P.P.M. acknowledge the support of the funding programs "Investissements d'avenir" ANR-10-IAIHU-06 and "Investissements d'avenir" ANR-11-INBS-0011-NeurATRIS: Translational Research Infrastructure for Biotherapies in Neurosciences. This work benefited from equipment and services from the CELIS core facility (Institut du Cerveau et de la Moelle Epinière, Paris). Dr. D.A.K. acknowledges support from the Canada Foundation for Innovation and the Natural Sciences and Engineering Research Council of Canada. Dr. E.J. received financial support from Herbal and Antioxidant Derivatives srl, Biano (RC), Italy, and from FFARB 2017 (Basic Research Activities Fund).