LY 354740

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.

Signaling Pathways >> GPCR/G Protein >> mGluR

Research Areas >> Neurological Disease

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].

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].

Mice[1] In Experiment 1A wild-type (female: N=6; male: N=5) and Gria1−/− mice (female: N=7; male: N=8) first receive 30 trials of drug-free testing (five trials per day for 6 days). Each animal is then tested on rewarded alternation following an injection of either LY354740 (15 mg/kg) or vehicle. After injection animals are returned to the home cage for 30 min before behavioural testing commenced. Each animal is given 10 trials of rewarded alternation in the T-maze. Mice are given a maximum of 120 s to a complete a trial. At least 24 h after the first round of drug testing the animals are re-tested in the absence of any drug treatment to ensure that there are no long-term effects of the drug, and that the mice maintain a high level of alternation performance. Twenty-four hours after this re-testing, mice receive a further 10 trials of rewarded alternation testing, but now under the drug condition that they have not previously received. The order of drug exposure is counterbalanced within genotype and sex as far as possible given the numbers of mice. In all stages, the number of trials in which the animal alternated, as well as time taken to run from the start arm to the food well on the sample run (sample latency), and the time taken to run from the start arm to making a choice on the choice run (choice latency), are recorded. Latencies are measured by the experimenter using a stopwatch. The experimenter is blind to the genotype and drug allocations of the animals throughout testing. In Experiment 1B, separate groups of male wild-type (N=7) and Gria1−/− mice (N=7) undgo the same procedure as Experiment 1A but now they receive either vehicle or a higher dose of LY354740 (30 mg/kg). Subsequently, in Experiment 1C, to investigate the potential effects of increased proactive interference, the procedure used in Experiment 1B is repeated in the same mice, using the same drug dose (30 mg/kg), but now using a modified testing protocol in which the interval between trials is reduced to 20 s. Rats[4] Two experiments are conducted. The first experiment compares the effects of LY354740 (10 mg/kg, i.p., neutralized to a pH ∼ 7.4) or vehicle (0.9% saline neutralized to pH ∼ 7.4) in rats remaining in their home cages or rats exposed to 2 h of immobilization stress in plastic cones (n=7, cage control/vehicle; n=7, cage control/LY354740; n=6, stress/vehicle; n=6, stress/LY354740). The second experiment compares two lower LY354740 doses (1 and 3 mg/kg, i.p.) or vehicle in rats exposed to a 2-h period of immobilization stress to rats treated with vehicle in their home cages (n=4 for all groups). All animals are injected with either LY354740 or vehicle 15 min prior to being placed in plastic cones with the open end securely closed. All immobilized rats are placed in plexiglass chamber with animal bedding on the bottom; brought to a quiet room outside of the animal colony; and immediately placed in a plastic cone. Two hours after being placed in the plastic containers, the rats are decapitated. The brains are removed and frozen on dry ice, and stored at −80°C.

[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.

mavoglurant | L-Glutamine | CTEP (RO4956371) | L-(+)Sodium glutamate | ADX-88178 | MPEP (Hydrochloride) | FITM | (S)-MCPG | Basimglurant | LY341495 | Dipraglurant | JNJ-40411813 | LY404039 | JNJ 16259685 | ADX-47273