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Chemical Compound Review

CTK8F0257     (1S,2S)-2-[(1R)-1-amino-1- carboxy-2-(2,6...

Synonyms: DCL000500, DNC000907, CID9796068, AC1O44IH, LY341495, ...
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Disease relevance of LY341495


Psychiatry related information on LY341495

  • Additionally, LY341495 alone increased PCP-induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR [6].
  • LY341495 alone increased waking by reducing NREM and REM sleep [7].
  • High doses of AVP4-9 exacerbated the PA task performance impairment induced by LY341495 (an mGluR2/3 antagonist), and PMA injection (1 mug) also exacerbated the impairment induced by the antagonist [8].

High impact information on LY341495

  • The mGluR3 and group II antagonists beta-NAAG and LY341495 blocked these actions [9].
  • The anti-allodynic effect induced by APDC was inhibited by pretreatment with LY341495, a group II mGluR antagonist [10].
  • Down-regulation of beta-adrenergic receptors occurred at shorter times (i.e. after 14 days) when imipramine was combined with low doses (0.5 mg/kg, i.p.) of the selective mGlu2/3 receptor agonist LY379268, or with the preferential mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.). Higher doses of LY379268 (2 mg/kg, i.p.) were inactive [11].
  • Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels [12].
  • To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co-administered with ZJ43 prior to PCP treatment [6].

Chemical compound and disease context of LY341495


Biological context of LY341495

  • In two selected cultures (MZC-12 and FCN-9), the mGlu2/3 receptor antagonist, LY341495, slowed cell proliferation when applied to the growth medium from the second day after plating [1].
  • 3. The depression of the CT EPSP caused by L-AP4 was reversed using the group III antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 1 mM), and the group II/III antagonist LY341495 (3 microM), but not using the group II antagonist (2S)-alpha-ethylglutamic acid (300 microM) [14].
  • The anti-proliferative effect of LY341495 was confirmed by measuring [methyl-3H]-thymidine incorporation in cultures arrested in G0 phase of the cell cycle and then stimulated to proliferate by the addition of 10% fetal calf serum or 100 ng/mL of epidermal growth factor (EGF) [1].
  • In rat hippocampal slices, LY341495 eliminated 30 microM DHPG-stimulated PI hydrolysis and 100 microM (1S,3R)-ACPD-inhibition of forskolin-stimulated cAMP formation at concentrations of 100 and 0.03 microM, respectively [15].
  • Among the human group III mGlu receptors, the most potent inhibition of L-2-amino-4-phosphonobutyric acid (L-AP4) responses was seen for LY341495 at mGlu8, with an IC50 of 0.17 microM [16].

Anatomical context of LY341495

  • 4. Neither MAP4 nor LY341495 had any effect on the CT EPSPs evoked by 10 Hz trains of five stimuli, indicating the lack of endogenous activation of group III mGlu receptors in the thalamus during short bursts of cortical input [14].
  • In contrast to LY341495, changes in c-Fos expression following LY354740 were more modest and not generally widespread (decreased in 1 region, dentate gyrus; and increased in 13 out of 52 regions) [17].
  • Although the rank order of potency of LY341495 was the same on native rat and cloned human mGlu receptors, there was a compression in the selectivity between group II and III mGlu receptors, expressed in the spinal cord [18].
  • The selective mGlu2/3 receptor antagonist LY341495 exacerbates behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons [19].
  • Field EPSPs evoked by optic tract stimulation under conditions of GABA receptor blockade were reduced by DCPG by up to 67.8+/-5.46% (EC(50) 1.25+/-0.56 microM), and this effect could be antagonised by LY341495 at a concentration (300 nM) known to be effective at mGlu8 receptors but not at mGlu4 or mGlu7 receptors [20].

Associations of LY341495 with other chemical compounds

  • Depression during the early, but not later part of the train was significantly greater in juvenile than adult rats and was blocked by the mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) [21].
  • The application of group II mGluR antagonist (LY341495) alone delayed the recovery of PGE2- and carrageenan-induced mechanical allodynia [22].
  • Activation of presynaptic group II mGlu autoreceptors by synaptically released glutamate, as revealed by a LY341495-mediated increase in the relative amplitude of a test fEPSP evoked after a conditioning burst, was observed in both the dentate gyrus and the stratum lacunosum of wild-type, but not mGlu2 -/- mice [23].
  • In contrast, LY341495 did not block the phosphoinositide hydrolysis response to MHI in rat cortical slices [24].
  • In addition, 1S,3R-ACPD-stimulated PI hydrolysis was no longer enhanced in imipramine-treated rats when the mGlu2/3 component of the PI response was abrogated by the antagonist, LY341495 [25].

Gene context of LY341495

  • In functional assays, we previously described LY341495 as a highly potent and selective mGlu2 and mGlu3 receptor antagonist [26].
  • LY341495 was less potent at mGlu7 (IC50 = 0.99 microM) and least potent at mGlu4 (IC50 = 22 microM) [16].
  • LTP proved insensitive to the selective mGluR2/3 antagonists (2S)-alpha-ethylglutamic acid and LY341495, either spinally or intravenously delivered [27].
  • Finally, we found that the novel mGluR antagonist LY341495 completely blocked the activation of mGluR1 and mGluR5 and blocked the phosphoinositide hydrolysis response to DHPG in rat cortical slices [24].
  • LY341495 competitively antagonised DHPG-stimulated PI hydrolysis in AV12-664 cells expressing either human mGlu1 or mGlu5 receptors with Ki-values of 7.0 and 7.6 microM, respectively [15].

Analytical, diagnostic and therapeutic context of LY341495

  • LY341495 also depressed low-frequency and stimulated high-frequency EEG power [7].
  • Pretreatment with LY379268 reduced cocaine self-administration and cocaine-induced reinstatement of drug seeking in a dose-dependent, LY341495-reversible manner [28].
  • Rats with implanted electrodes were injected with 1, 5, or 10 mg/kg LY341495 at hour 5.5 of the dark period [7].
  • MGS0039 (0.3-3 mg/kg, i.p.) as well as LY341495 (0.1-3 mg/kg, i.p.) had dose-dependent antidepressant-like effects in the rat forced swim test and in the mouse tail suspension test [29].
  • This hyperlocomotor response was absent in rats tested with a combination of LY341495 and the group II mGluR agonist LY379268 (1.0mg/kg, i.p.). In a second experiment, different rats were tested following microinjections into the NAcc (saline or LY341495, 0.1, 10 or 100mug/0.5mul/side) [30].


  1. Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. D'Onofrio, M., Arcella, A., Bruno, V., Ngomba, R.T., Battaglia, G., Lombari, V., Ragona, G., Calogero, A., Nicoletti, F. J. Neurochem. (2003) [Pubmed]
  2. The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy. Ngomba, R.T., Biagioni, F., Casciato, S., Willems-van Bree, E., Battaglia, G., Bruno, V., Nicoletti, F., van Luijtelaar, E.L. Neuropharmacology (2005) [Pubmed]
  3. Modulation of stress-induced and stimulated hyperprolactinemia with the group II metabotropic glutamate receptor selective agonist, LY379268. Johnson, M.P., Chamberlain, M. Neuropharmacology (2002) [Pubmed]
  4. Group II metabotropic glutamate receptors regulate the vulnerability to hypoxic brain damage. Poli, A., Beraudi, A., Villani, L., Storto, M., Battaglia, G., Di Giorgi Gerevini, V., Cappuccio, I., Caricasole, A., D'Onofrio, M., Nicoletti, F. J. Neurosci. (2003) [Pubmed]
  5. Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo. Arcella, A., Carpinelli, G., Battaglia, G., D'Onofrio, M., Santoro, F., Ngomba, R.T., Bruno, V., Casolini, P., Giangaspero, F., Nicoletti, F. Neuro-oncology (2005) [Pubmed]
  6. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. Olszewski, R.T., Bukhari, N., Zhou, J., Kozikowski, A.P., Wroblewski, J.T., Shamimi-Noori, S., Wroblewska, B., Bzdega, T., Vicini, S., Barton, F.B., Neale, J.H. J. Neurochem. (2004) [Pubmed]
  7. The metabotropic glutamate (mGLU)2/3 receptor antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid] stimulates waking and fast electroencephalogram power and blocks the effects of the mGLU2/3 receptor agonist ly379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] in rats. Feinberg, I., Schoepp, D.D., Hsieh, K.C., Darchia, N., Campbell, I.G. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  8. Ameliorative and exacerbating effects of [pGlu(4),Cyt(6)]AVP((4-9)) on impairment of step-through passive avoidance task performance by group II metabotropic glutamate receptor-related drugs in mice. Sato, T., Ishida, T., Tanaka, K., Ohnishi, Y., Irifune, M., Mimura, T., Nishikawa, T. J. Pharmacol. Sci. (2005) [Pubmed]
  9. Differential negative coupling of type 3 metabotropic glutamate receptor to cyclic GMP levels in neurons and astrocytes. Wroblewska, B., Wegorzewska, I.N., Bzdega, T., Olszewski, R.T., Neale, J.H. J. Neurochem. (2006) [Pubmed]
  10. Role of peripheral group I and II metabotropic glutamate receptors in IL-1beta-induced mechanical allodynia in the orofacial area of conscious rats. Ahn, D.K., Kim, K.H., Jung, C.Y., Choi, H.S., Lim, E.J., Youn, D.H., Bae, Y.C. Pain (2005) [Pubmed]
  11. Metabotropic glutamate receptors and neuroadaptation to antidepressants: imipramine-induced down-regulation of beta-adrenergic receptors in mice treated with metabotropic glutamate 2/3 receptor ligands. Matrisciano, F., Scaccianoce, S., Del Bianco, P., Panaccione, I., Canudas, A.M., Battaglia, G., Riozzi, B., Ngomba, R.T., Molinaro, G., Tatarelli, R., Melchiorri, D., Nicoletti, F. J. Neurochem. (2005) [Pubmed]
  12. In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands. Smolders, I., Lindekens, H., Clinckers, R., Meurs, A., O'Neill, M.J., Lodge, D., Ebinger, G., Michotte, Y. J. Neurochem. (2004) [Pubmed]
  13. Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice. O'Neill, M.F., Heron-Maxwell, C., Conway, M.W., Monn, J.A., Ornstein, P. Neuropharmacology (2003) [Pubmed]
  14. Group III metabotropic glutamate receptors control corticothalamic synaptic transmission in the rat thalamus in vitro. Turner, J.P., Salt, T.E. J. Physiol. (Lond.) (1999) [Pubmed]
  15. The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity. Fitzjohn, S.M., Bortolotto, Z.A., Palmer, M.J., Doherty, A.J., Ornstein, P.L., Schoepp, D.D., Kingston, A.E., Lodge, D., Collingridge, G.L. Neuropharmacology (1998) [Pubmed]
  16. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Kingston, A.E., Ornstein, P.L., Wright, R.A., Johnson, B.G., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D. Neuropharmacology (1998) [Pubmed]
  17. Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo. Linden, A.M., Bergeron, M., Schoepp, D.D. Neuropharmacology (2005) [Pubmed]
  18. Actions of LY341495 on metabotropic glutamate receptor-mediated responses in the neonatal rat spinal cord. Howson, P.A., Jane, D.E. Br. J. Pharmacol. (2003) [Pubmed]
  19. The selective mGlu2/3 receptor antagonist LY341495 exacerbates behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons. Rasmussen, K., Hsu, M.A., Vandergriff, J. Neuropharmacology (2004) [Pubmed]
  20. Reduction of excitatory transmission in the retino-collicular pathway via selective activation of mGlu8 receptors by DCPG. Pothecary, C.A., Jane, D.E., Salt, T.E. Neuropharmacology (2002) [Pubmed]
  21. Metabotropic glutamate receptors modulate feedback inhibition in a developmentally regulated manner in rat dentate gyrus. Doherty, J.J., Alagarsamy, S., Bough, K.J., Conn, P.J., Dingledine, R., Mott, D.D. J. Physiol. (Lond.) (2004) [Pubmed]
  22. Peripheral group II metabotropic glutamate receptors mediate endogenous anti-allodynia in inflammation. Yang, D., Gereau, R.W. Pain (2003) [Pubmed]
  23. Differential regulation of synaptic transmission by mGlu2 and mGlu3 at the perforant path inputs to the dentate gyrus and CA1 revealed in mGlu2 -/- mice. Kew, J.N., Pflimlin, M.C., Kemp, J.A., Mutel, V. Neuropharmacology (2002) [Pubmed]
  24. 4-Methylhomoibotenic acid activates a novel metabotropic glutamate receptor coupled to phosphoinositide hydrolysis. Chung, D.S., Traynelis, S.F., Murphy, T.J., Conn, P.J. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  25. Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus. Matrisciano, F., Storto, M., Ngomba, R.T., Cappuccio, I., Caricasole, A., Scaccianoce, S., Riozzi, B., Melchiorri, D., Nicoletti, F. Neuropharmacology (2002) [Pubmed]
  26. [3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells. Johnson, B.G., Wright, R.A., Arnold, M.B., Wheeler, W.J., Ornstein, P.L., Schoepp, D.D. Neuropharmacology (1999) [Pubmed]
  27. Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group I, but not group II/III metabotropic glutamate receptors. Azkue, J.J., Liu, X.G., Zimmermann, M., Sandkühler, J. Pain (2003) [Pubmed]
  28. Pharmacological stimulation of group ii metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys. Adewale, A.S., Platt, D.M., Spealman, R.D. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  29. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Chaki, S., Yoshikawa, R., Hirota, S., Shimazaki, T., Maeda, M., Kawashima, N., Yoshimizu, T., Yasuhara, A., Sakagami, K., Okuyama, S., Nakanishi, S., Nakazato, A. Neuropharmacology (2004) [Pubmed]
  30. Blockade of group II metabotropic glutamate receptors in the nucleus accumbens produces hyperlocomotion in rats previously exposed to amphetamine. Chi, H., Jang, J.K., Kim, J.H., Vezina, P. Neuropharmacology (2006) [Pubmed]
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