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Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans

Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Grillon, Christian; Cordova, Jeremy; Levine, Louise R.; Morgan, Charles A., III (Mood and Anxiety Disorder Program, NIMH/NIH/DHHS, MSC 2670, Bethesda, MD 20892-2670, USA).Chemical with cas number 176199-48-7 also plays role. Psychopharmacology (Berlin, Germany), 168(4), 446-454 (English) 2003 Springer-Verlag. CODEN: PSCHDL. ISSN: 0033-3158. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) LY354740, a structural analog of glutamate that shows specificity at the mGluR2/3 receptor, has anxiolytic effects in animal models. This study investigated the anxiolytic effects of LY354740 in humans using the fear-potentiated startle reflex methodol. Subjects were given either placebo (n=16), 20 mg LY354740 (n=15), or 200 mg LY354740 (n=13). The fear-potentiated startle tests examd. startle potentiation to shock anticipation and to darkness. Consistent with previous results, startle was increased by threat of shock and by darkness. LY354740 did not affect baseline startle. Correspondingly, subjects did not report LY354740 to be sedative. LY354740 significantly reduced the increase in startle magnitude during shock anticipation, but not during darkness. Subjective reports of state anxiety and neg. affectivity during the fear-potentiated startle tests were also reduced in a dose-dependent manner by LY354740. These results suggest that LY354740 has an anxiolytic profile in humans without being sedative. .

Activation of Group II and Group III metabotropic glutamate receptors by endogenous ligand(s) and the modulation of synaptic transmission in the superficial superior colliculus

Activation of Group II and Group III metabotropic glutamate receptors by endogenous ligand(s) and the modulation of synaptic transmission in the superficial superior colliculus. Thompson, H.; Neale, S. A.; Salt, T. E. (Division of Visual Science, Institute of Ophthalmology, University College London, London EC1V 9EL, UK). Neuropharmacology, 47(6), 822-832 (English) 2004 Elsevier B.V. CODEN: NEPHBW. ISSN: 0028-3908.There are some reagents with their cas registry numbers 56-86-0 and 176199-48-7 are used in this study. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) Previous work from this lab. indicates that Group II/III metabotropic glutamate (mGlu) receptors modulate responses of SC neurons to visual stimuli in vivo. It is thought that tonic levels of glutamate may be sufficient to activate some mGlu receptors. The authors wished to investigate if these receptors are activated under ambient conditions in SC. Field excitatory postsynaptic potentials (fEPSPs) evoked by optic tract stimulation were recorded from 300 mm slices of the adult pigmented rat superior colliculus at 34°. The Group II receptor selective agonist LY354740 (100-300 nM) had no significant effect on the peak amplitude of the fEPSP, although it did enhance the late phase of the fEPSP. To test for activation of Group II receptors by endogenous ligand, the selective antagonists LY341495 (50 nM) or EGLU (200 mM) were applied: these either enhanced or reduced the fEPSP amplitude. In similar expts. carried out at 22°, no effect was seen. The fEPSP enhancements, but not the fEPSP redns., could be occluded by GABA antagonists. Application of higher concns. of LY341495 (300, 600 nM-known to also affect Group III receptors, particularly mGlu8), or co-application of 50 nM LY341495 and the Group III-selective antagonist CPPG (100 mM) produced enhancements of responses, or counteracted response redns. over those seen with 50 nM LY341495 alone. The predominant Group II receptor in SC is mGlu3. It is known that this can be located presynaptically on GABAergic and glutamatergic terminals, postsynaptically, and on glia. The authors' results indicate that such receptors are tonically activated by endogenous transmitter, have distinct effects, and influence retino-collicular transmission. Furthermore, there is a segregation of effects where receptors exert some of their effects via modulation of GABAergic circuitry. .