LY 354740

LY354740 is a highly potent, efficacious and selective group II (mGlu2/3) receptor agonist, used for treatment of anxiety and stress-related disorders.

In Vitro:LY354740 down-regulates spots 1014, 1822 (hypoxia up-regulated protein 1), 4513 (an isoform of protein disulfide isomerase 3), 6204, 6312, 7306 (26S proteasome non-ATPase regulatory subunit 7) and protein spots 1013 and 6005 (destrin), and up-regulates spot 6507 (collapsin response mediator protein 1) in mouse cortical neurons[2].

In Vivo:LY354740 (15 or 30 mg/kg, i.p.) has no effect on spatial working memory performance in Gria1−/− or WT mice, and it has no effect on rewarded alternation testing with a short inter-trial interval in Gria1−/− and WT mice at concentration of 30 mg/kg. LY354740 (15 or 30 mg/kg, i.p.) reduces spontaneous locomotor activity in wild-type and Gria1−/− mice[1]. LY354740 (15 mg/kg, i.p.) dreases novelty-induced hyperlocomotion in naive GluA1-KO and pre-handled GluA1-KO males, but not in females. LY354740 (15 mg/kg, i.p.) significantly reduces the increased c-Fos expression of GluA1-KO males to the level of WT males, but not in of females[3]. LY354740 (10 mg/kg, i.p.) attenuates the immobilization stress-induced increase in BDNF mRNA expression in the rat mPFC[4].

References:
[1]. Boerner T, et al. The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice. Eur J Neurosci. 2017 Apr;45(7):912- [2]. Orlando R, et al. Levels of the Rab GDP dissociation inhibitor (GDI) are altered in the prenatal restrain stress mouse model of schizophrenia and are differentially regulated by the mGlu2/3 receptor agonists, LY379268 and LY354740. Neuropharmacology. 2014 [3]. Procaccini C, et al. Reversal of novelty-induced hyperlocomotion and hippocampal c-Fos expression in GluA1 knockout male mice by the mGluR2/3 agonist LY354740. Neuroscience. 2013 Oct 10;250:189-200. [4]. Lee Y, et al. The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Neurosci Lett. 2006 May 8;398(3):328-32.

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models.[Pubmed:10608278]

Neuropharmacology. 1999 Dec;38(12):1831-9.

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.

Absence of direct effects on the dopamine D2 receptor by mGluR2/3-selective receptor agonists LY 354,740 and LY 379,268.[Pubmed:20506301]

Synapse. 2011 Jan;65(1):64-8.

We previously reported the absence of high-affinity binding of the group II metabotropic glutamate receptor agonists LY 354,740 and LY 379,268 to the D2L dopamine receptor. A rebuttal to our findings has since been reported (see Introduction section); this study represents our response. Analysis by LCMS of LY 354,740 and LY 379,268 used in this study revealed the correct molecular mass for these compounds. Both LY 354,740 and LY 379,268 exhibited potent agonist activity for mGluR(2) in the (3)(5)S-GTPgammaS assay. Functionally, neither compound displayed antagonist activity in the GTPgammaS assay with recombinant D(2). At concentrations up to 10 muM, both compounds failed to displace [(3)H]-raclopride, [(3)H]-PHNO, or [(3)H]-domperidone in filter-binding assays under isotonic (120 mM NaCl or N-methyl glucamine) or low-ionic strength (no NaCl or N-methyl glucamine) conditions. Some displacement of [(3)H]-domperidone (20-40%) was observed at 30 muM of LY 354,740 under low-ionic strength and under isotonic conditions in the absence of NaCl. No displacement of [(3)H]-domperidone was detected in a two site model at lower (<100 nM) concentrations of either compound. Moreover, no D(2) activity was observed for LY 354,740 or LY 379,268 in the CellKey (cellular dielectric spectroscopy) assay. In this communication, we discuss the possible reasons for differences in our study and the previously published work and implications of these studies for mechanisms of antipsychotic action.

LY-354740 (Eli Lilly).[Pubmed:12789623]

IDrugs. 2003 Jan;6(1):66-71.

Lilly is developing LY-354740, the lead compound in a series of derivatives of the metabotropic glutamate receptor group II agonist L-CCG-1, for the potential treatment of anxiety [212536], [276941], [276942].

Dopamine partial agonist actions of the glutamate receptor agonists LY 354,740 and LY 379,268.[Pubmed:18000815]

Synapse. 2008 Feb;62(2):154-8.

Because glutamate compounds alter the release of dopamine and prolactin, the present study examined whether group II metabotropic receptor agonists, LY 354,740 and LY 379,268, had any direct in vitro action on dopamine D2 receptors on rat striatal tissue, cloned D2Long receptors, and prolactin release from anterior pituitary cells. In competition versus the D2-specific ligand [(3)H]domperidone, LY 354,740 had a dissociation constant of 24 nM at D2(High) (the functional high-affinity state of dopamine D2 receptors), while the value for LY 379,268 was 21 nM. LY 354,740 also stimulated by 50% the incorporation of [(35)S]-GTP-gamma-S at a concentration of 120 nM, but its maximal stimulation was only 22% of the maximum elicited by dopamine. LY 379,268 stimulated by 50% the incorporation of [(35)S]-GTP-gamma-S at 280 nM, but its maximal stimulation was also only 22% of the maximum elicited by dopamine. However, both LY 354,740 and LY 379,268 potently inhibited the dopamine-induced incorporation of [(35)S]-GTP-gamma-S with inhibitory Ki values of 43 nM and 30 nM, respectively. The release of prolactin from rat isolated anterior pituitary cells in culture was 50% inhibited by 20 nM LY 379,268 and by 100 nM LY 354,740. These Ki values are similar to those known for the mGluR II receptor, suggesting that these compounds may have both glutamate and dopamine actions in vivo. The dopamine agonist and antagonist actions of these compounds indicate that these drugs have properties of a dopamine partial agonist, and may, therefore, have antipsychotic action.

Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors.[Pubmed:9454811]

J Pharmacol Exp Ther. 1998 Feb;284(2):651-60.

LY354740 is a conformationally constrained analog of glutamate which is a potent agonist for group II cAMP coupled metabotropic glutamate receptors (mGluRs). The discovery of this novel pharmacological agent has allowed the exploration of the functional consequences of activating group II mGluRs in vivo. In an effort to evaluate the clinical utility of LY354740 as an anxiolytic, we examined its effects in the fear potentiated startle and elevated plus maze models of anxiety and compared the results with the clinically prescribed anxiolytic diazepam. In the fear potentiated startle and elevated plus maze models, both LY354740 and diazepam produced significant anxiolytic activity (ED50 values of 0.3 and 0.4 mg/kg p. o. for fear potentiated startle and 0.2 and 0.5 mg/kg for the elevated plus maze, respectively). The duration of pharmacological effect for LY354740 in the efficacy models was 4 to 8 hr. In contrast to diazepam, acute administration of LY354740 did not produce sedation, cause deficits in neuromuscular coordination, interact with central nervous system depressants, produce memory impairment or change convulsive thresholds at doses 100- to 1000-fold the efficacious doses in animal models of anxiety. Thus, LY354740 has anxiolytic activity in animal models that are sensitive to benzodiazepines such as diazepam. However, at anxiolytic doses in these models, LY354740 produced none of the unwanted secondary pharmacology associated with diazepam. These data indicate a functional role for group II mGluRs in fear/anxiety responses in animals and suggest that compounds in this class may be beneficial in the treatment of anxiety-related disorders in humans without the side effects seen with currently prescribed medications.

LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors.[Pubmed:9144636]

Neuropharmacology. 1997 Jan;36(1):1-11.

The novel compound LY354740 is a conformationally constrained analog of glutamate, which was designed for interaction at metabotropic glutamate (mGlu) receptors. In this paper the selectivity of LY354740 for recombinant human mGlu receptor subtypes expressed in non-neuronal (RGT) cells is described. At human mGlu2 receptors, LY354740 produced > 90% suppression of forskolin-stimulated cAMP formation with an EC50 of 5.1 +/- 0.3 nM. LY354740 was six-fold less potent in activating human mGlu3 receptors (EC50 = 24.3 +/- 0.5 nM). LY354740 inhibition of forskolin-stimulated cAMP formation in human mGlu2 receptor-expressing cells was blocked by competitive mGlu receptor antagonists, including (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) and LY307452 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid). LY354740 had no agonist or antagonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu receptors) (EC50 > 100,000 nM). When tested at group I phosphoinositide-coupled human mGlu receptors (mGlu1a and mGlu5a), LY354740 did not activate or inhibit mGlu receptor agonist-evoked phosphoinositide hydrolysis at up to 100,000 nM. Electrophysiological experiments also demonstrated that LY354740 also had no appreciable activity in cells expressing human recombinant AMPA (GluR4) and kainate (GluR6) receptors. Thus, LY354740 is a highly potent, efficacious and selective group II (mGlu2/3) receptor agonist, useful to explore the functions of these receptors in situ.

Eglumegad (LY354740) is a highly potent and selective group II (mGlu2/3) receptor agonist with IC50s of 5 and 24 nM on transfected human mGlu2 and mGlu3 receptors, respectively.

LY 354740,176199-48-7,Eglumegad; Eglumetad,Natural Products,GluR, buy LY 354740 , LY 354740 supplier , purchase LY 354740 , LY 354740 cost , LY 354740 manufacturer , order LY 354740 , high purity LY 354740