This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g., 3) potentiate glutamate, shifting agonist potency by 2-fold. This effect was specific for mGlu2 (vs mGlu1,3-8 receptors). Also, 3 failed to potentiate a chimeric mGlu2/1 receptor, demonstrating the mGlu2 transmembrane region's critical involvement. In a fear-potentiated startle model, 3 showed anxiolytic activity that was prevented by mGlu2/3 antagonist pretreatment. Thus, these pyridylmethylsulfonamides represent the first mGlu2 receptor potentiators discovered.

Antidepressant-like effects of metabotropic glutamate (mGlu)5 receptor antagonists have been reported previously. We now provide definitive identification of mGlu5 receptors as a target for these effects through the combined use of selective antagonists and mice with targeted deletion of the mGlu5 protein. In these experiments, the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the more selective and metabolically stable analog 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) decreased immobility in the mouse forced swim test, a test predictive of antidepressant efficacy in humans. mGlu5 receptor knockout mice had a phenotype in the forced swim test that was congruent with the effects of receptor blockade; mGlu5 receptor knockout mice were significantly less immobile than their wild-type counterparts. Consistent with mGlu5 receptor mediation of the antidepressant-like effects of MPEP, the effects of MPEP were not observed in mGlu5 receptor knockout mice, whereas comparable effects of the tricyclic antidepressant imiprimine remained active in the mutant mice. MPEP and imiprimine resulted in a synergistic antidepressant-like effect in the forced swim test. The drug interaction was not likely because of increased levels of drugs in the brain, suggesting a pharmacodynamic interaction of mGlu5 and monoaminergic systems in this effect. Thus, the present findings substantiate the hypothesis that mGlu5 receptor antagonism is associated with antidepressant-like effects. This mechanism may not only provide a novel approach to the therapeutic management of depressive disorders but also may be useful in the augmentation of effects of traditional antidepressant agents.Monoamine-based antidepressants have been the primary pharmacological approach to the treatment of mood disorders, but these agents suffer from some limitations in both safety and efficacy that have prompted the continued search for novel therapeutic targets beyond the monoamine system (cf., Skolnick et al., 2001). Glutamate, the major excitatory neurotransmitter used by the mammalian brain, binds to both ion channel-associated (iontropic) and G protein-coupled (metabotropic) receptor subtypes. The glutamatergic system plays a critical role in the pathophysiology of depression and in the action of antidepressant drugs (Skolnick et al., 2001;Kugaya and Sanacora, 2005;Alt et al., 2006). Modulation of ionotropic (e.g., AMPA receptors and NMDA receptors) and metabotropic glutamate (mGlu) receptors (see below) produces antidepressant-like effects in preclinical models. The involvement of ionotropic glutamate receptors in the control of mood disorders and the mechanism of antidepressants has been studied much more extensively than the metabotropic glutamate receptors. However, recent attention has been directed to the potential role of the mGlu receptors.The mGlu receptors are classified into three groups, with eight subtypes: group I (mGlu1 and -5), group II (mGlu2 and -3), and group III (mGlu4, (Schoepp and Conn, 1993) base...

The activation of both mGlu2 and mGlu3 receptors by LY354740 appears to be required for anxiolytic-like activity in the EPM test in mice. These studies serve as a foundation for additional studies on underlying circuits, brain structures, and receptor subtypes involved in the anxiolytic-like actions of mGlu receptor active agents, and the design of future drugs for anxiety disorders in humans.

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The genetic composition of 11 high-yielding recombinants of influenza virus was determined by polyacrylamide gel electrophoresis of the 32P-labeled RNAs obtained from the recombinants and their parental viruses. The high-yield recombinants that were selected for potential use as vaccine strains contained the surface hemagglutinin and neuraminidase antigens of the low-yielding parental viruses. The increased growth capacity of the recombinants is associated with the presence of genes derived from the high-yielding laboratory strain A/Puerto Rico/8/34. Although increased growth capacity in these recombinants could not be attributed to specific genes or gene combinations, all of the high-yielding recombinants examined derived the M gene from the A/Puerto Rico/8/34 parent.