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Chemical Compound Review

Eglumegad     (1S,2S,5R,6S)-2- aminobicyclo[3.1.0]hexane...

Synonyms: Eglumetad, CHEMBL8759, PubChem18158, SureCN481248, AG-E-26589, ...
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Disease relevance of LY354740

  • The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model with application at 0, 1, and 2 weeks after OHT surgery and the effects assessed as described before [1].
  • Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound [2].
  • Furthermore, LY354740 did not attenuate oxygen-glucose deprivation-induced neuronal death in vitro or ischemic infarction after transient middle cerebral artery occlusion in rats [3].
  • The group II selective agonists DCG-IV and LY354740 reduced light-evoked excitatory postsynaptic currents (EPSCs) in ganglion cells [4].
  • The present results suggest that LY354740 counteracts the muscle rigidity in an animal model of parkinsonism [5].

Psychiatry related information on LY354740

  • Doses of LY354740 and LY379268 that blocked the effects on PCP had no effects on rotorod performance, and (with the exception of rearing behavior) had minimal effects on AMP-evoked motor activities [6].

High impact information on LY354740

  • To investigate whether these receptors interact to regulate ACh release, LY354740 (a group-II mGlu receptor agonist) and NMDA were co-applied in striatal synaptosomes and slices [7].
  • LY354740 prevented the NMDA-evoked [3H]-choline release from synaptosomes and ACh release from slices [7].
  • The novel mGluR agonist LY354740 and a related analogue LY379268 are selective for mGluR2/3 receptors and are centrally active after systemic administration [8].
  • These results show the important functional involvement of the limbic system together with the participation of components of different sensory systems in response to the activation of mGluR2 and mGluR3 with LY354740 and LY379268 [8].
  • After LY354740 (3.0mg/kg), 4 of the 42 regions measured showed statistically significant changes from vehicle-treated controls: red nuclei (-16%), mammillary body (-25%), anterior thalamus (-29%), and the superficial layer of the superior colliculus (+50%) [8].

Biological context of LY354740

  • RESULTS: All strategies of glutamate modulation reduced SSP-induced-RGC apoptosis compared with the control, in a dose-dependent manner: MK801 (R2= 0.8863), ifenprodil (R2= 0.4587), and LY354740 (R2= 0.9094), with EC50s of 0.074, 0.0138, and 19 nanomoles, respectively [1].
  • In striatal brain slices, LY354740 inhibited evoked excitatory postsynaptic potentials (EPSPs) equally well following either a low- (0.06 Hz) or high (4 Hz)-frequency stimulation of corticostriatal afferents [9].
  • Interestingly, despite the slightly lower potency ( approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments [10].
  • However, LY354740, applied following the induction of long-term potentiation by high frequency stimulation, resulted in additional long-term potentiation [11].
  • The selective Group II agonists LY354740 (1-10 microM) and N-acetyl-aspartyl-glutamate (NAAG; 100-500 microM) both caused a reversible depression of these monosynaptic TRN IPSPs without any effect on membrane potential or input resistance [12].

Anatomical context of LY354740

  • Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions [13].
  • The present study utilized in vivo microdialysis to examine the effects of LY354740 on extracellular monoamine levels in the medial prefrontal cortex (mPFC) of animals subjected to 30 min immobilization stress [14].
  • LY354740 administration significantly increased c-Fos expression in specific limbic regions, including the lateral division of the central nucleus of the amygdala (CeL), lateral parabrachial nucleus, locus coeruleus, and Edinger-Westphal nucleus, whether or not animals were exposed to the EPM [13].
  • Moreover, LY354740 administration per se significantly increased c-Fos expression in regions processing sensory information, including the paraventricular and lateral geniculate nucleus of the thalamus as well as the nucleus of the optic tract and superior colliculus [13].
  • 4. In Golgi cells of the cerebellum and interneurones of the accessory olfactory bulb, which also express group II mGluRs, LY354740 did not induce GIRK activation but inhibited voltage-gated Ca2+ channel currents [15].

Associations of LY354740 with other chemical compounds

  • Quisqualic acid and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) were selected for mGlu1R, dicarboxycyclopropylglycine (DCG-IV), LY354740, (S)-4-carboxyphenylglycine (4CPG) for mGlu2R, and (S)-2-amino-4-phosphonobutyric acid (AP4), 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), (S)-4-phosphonophenylglycine (PPG) for mGlu4R [16].
  • Interestingly, although LY354740 is anxiolytic in animals, LY341495 did not increase c-Fos expression in the paraventricular nucleus of the hypothalamus which is usually activated by stress/fear and several anxiogenic compounds [17].
  • Thus, LY354740 has anxiolytic activity in animal models that are sensitive to benzodiazepines such as diazepam [18].
  • Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results [19].
  • 3. In experiment 1, LY354740 (1 and 10, but not 0.1 mg kg(-1)) as well as the reference compound, an uncompetitive NMDA receptor antagonist memantine (7.5 mg kg(-1)) inhibited the development of morphine tolerance [20].

Gene context of LY354740

  • Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10) [21].
  • At human mGlu2 receptors, LY354740 produced > 90% suppression of forskolin-stimulated cAMP formation with an EC50 of 5.1 +/- 0.3 nM [22].
  • LY354740 was six-fold less potent in activating human mGlu3 receptors (EC50 = 24.3 +/- 0.5 nM) [22].
  • LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM) [22].
  • The mGluR3 and group II agonists FN6 and LY354740 had similar effects on cGMP levels [23].

Analytical, diagnostic and therapeutic context of LY354740

  • LY354740 is a potent and selective agonist for group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3 receptors, with anxiolytic activity in several animal models of anxiety, including the elevated plus maze (EPM) test [13].
  • (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials [24].
  • 1. The effects of the group II metabotropic glutamate receptor (mGluR) agonists DCG-IV and LY354740 were examined in neurones freshly dissociated from the rat cerebellum and olfactory bulb, using the whole-cell configuration of the patch-clamp technique [15].
  • Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model [2].
  • Perfusion of either of two potent mGluRII agonists, (2S,1R,2R,3R)-2-(2S, 1'R, 2'R, 3'R)-2 (2' 3'-dicarboxycyclopropyl)glycine (DCG-IV) or (+)-2- aminobicyclo[3.1.0]hexane-2-6-dicarboxylic acid (LY354740) induced a reversible inhibition of the field EPSP followed, upon washout of the agonist, by LTD [25].


  1. Assessment of neuroprotective effects of glutamate modulation on glaucoma-related retinal ganglion cell apoptosis in vivo. Guo, L., Salt, T.E., Maass, A., Luong, V., Moss, S.E., Fitzke, F.W., Cordeiro, M.F. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  2. Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344. Rorick-Kehn, L.M., Perkins, E.J., Knitowski, K.M., Hart, J.C., Johnson, B.G., Schoepp, D.D., McKinzie, D.L. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  3. Selective activation of group II mGluRs with LY354740 does not prevent neuronal excitotoxicity. Behrens, M.M., Strasser, U., Heidinger, V., Lobner, D., Yu, S.P., McDonald, J.W., Won, M., Choi, D.W. Neuropharmacology (1999) [Pubmed]
  4. Activation of group II metabotropic glutamate receptors inhibits glutamate release from salamander retinal photoreceptors. Higgs, M.H., Lukasiewicz, P.D. Vis. Neurosci. (2002) [Pubmed]
  5. LY354740, a group II metabotropic glutamate receptor agonist with potential antiparkinsonian properties in rats. Konieczny, J., Ossowska, K., Wolfarth, S., Pilc, A. Naunyn Schmiedebergs Arch. Pharmacol. (1998) [Pubmed]
  6. The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. Cartmell, J., Monn, J.A., Schoepp, D.D. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  7. Group-II metabotropic glutamate receptors negatively modulate NMDA transmission at striatal cholinergic terminals: role of P/Q-type high voltage activated Ca++ channels and endogenous dopamine. Mela, F., Marti, M., Fiorentini, C., Missale, C., Morari, M. Mol. Cell. Neurosci. (2006) [Pubmed]
  8. Group II selective metabotropic glutamate receptor agonists and local cerebral glucose use in the rat. Lam, A.G., Monn, J.A., Schoepp, D.D., Lodge, D., McCulloch, J. J. Cereb. Blood Flow Metab. (1999) [Pubmed]
  9. Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Johnson, M.P., Barda, D., Britton, T.C., Emkey, R., Hornback, W.J., Jagdmann, G.E., McKinzie, D.L., Nisenbaum, E.S., Tizzano, J.P., Schoepp, D.D. Psychopharmacology (Berl.) (2005) [Pubmed]
  10. Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of Agonist (-)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic Acid (LY404039). Rorick-Kehn, L.M., Johnson, B.G., Burkey, J.L., Wright, R.A., Calligaro, D.O., Marek, G.J., Nisenbaum, E.S., Catlow, J.T., Kingston, A.E., Giera, D.D., Herin, M.F., Monn, J.A., McKinzie, D.L., Schoepp, D.D. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  11. Activation of group II metabotropic glutamate receptors results in long-term potentiation following preconditioning stimulation in the dentate gyrus. Rush, A.M., Wu, J., Rowan, M.J., Anwyl, R. Neuroscience (2001) [Pubmed]
  12. Group II and III metabotropic glutamate receptors and the control of the nucleus reticularis thalami input to rat thalamocortical neurones in vitro. Turner, J.P., Salt, T.E. Neuroscience (2003) [Pubmed]
  13. Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions. Linden, A.M., Greene, S.J., Bergeron, M., Schoepp, D.D. Neuropsychopharmacology (2004) [Pubmed]
  14. The mGlu2/3 receptor agonist, LY354740, blocks immobilization-induced increases in noradrenaline and dopamine release in the rat medial prefrontal cortex. Swanson, C.J., Perry, K.W., Schoepp, D.D. J. Neurochem. (2004) [Pubmed]
  15. Metabotropic glutamate group II receptors activate a G protein-coupled inwardly rectifying K+ current in neurones of the rat cerebellum. Knoflach, F., Kemp, J.A. J. Physiol. (Lond.) (1998) [Pubmed]
  16. Common and selective molecular determinants involved in metabotopic glutamate receptor agonist activity. Bertrand, H.O., Bessis, A.S., Pin, J.P., Acher, F.C. J. Med. Chem. (2002) [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. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. Helton, D.R., Tizzano, J.P., Monn, J.A., Schoepp, D.D., Kallman, M.J. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  19. Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results. Kellner, M., Muhtz, C., Stark, K., Yassouridis, A., Arlt, J., Wiedemann, K. Psychopharmacology (Berl.) (2005) [Pubmed]
  20. Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice. Popik, P., Kozela, E., Pilc, A. Br. J. Pharmacol. (2000) [Pubmed]
  21. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. Monn, J.A., Valli, M.J., Massey, S.M., Hansen, M.M., Kress, T.J., Wepsiec, J.P., Harkness, A.R., Grutsch, J.L., Wright, R.A., Johnson, B.G., Andis, S.L., Kingston, A., Tomlinson, R., Lewis, R., Griffey, K.R., Tizzano, J.P., Schoepp, D.D. J. Med. Chem. (1999) [Pubmed]
  22. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Schoepp, D.D., Johnson, B.G., Wright, R.A., Salhoff, C.R., Mayne, N.G., Wu, S., Cockerman, S.L., Burnett, J.P., Belegaje, R., Bleakman, D., Monn, J.A. Neuropharmacology (1997) [Pubmed]
  23. 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]
  24. Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. Bueno, A.B., Collado, I., de Dios, A., Domínguez, C., Martín, J.A., Martín, L.M., Martínez-Grau, M.A., Montero, C., Pedregal, C., Catlow, J., Coffey, D.S., Clay, M.P., Dantzig, A.H., Lindstrom, T., Monn, J.A., Jiang, H., Schoepp, D.D., Stratford, R.E., Tabas, L.B., Tizzano, J.P., Wright, R.A., Herin, M.F. J. Med. Chem. (2005) [Pubmed]
  25. Activation of mGluRII induces LTD via activation of protein kinase A and protein kinase C in the dentate gyrus of the hippocampus in vitro. Huang, L., Killbride, J., Rowan, M.J., Anwyl, R. Neuropharmacology (1999) [Pubmed]
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