LY 379268 is a highly selective and blood-brain barrier-permeable type II mGlu receptor agonist with EC50 values of 2.69 and 4.48nM for hmGlu2 and hmGlu3, respectively [1]. mGluRs are glutamate receptors and are considered as therapeutic targets for neurodegenerative diseases [2]. LY 379268 has antioxidant and neuroprotective effects [3].
In vitro, LY 379268 (0.1, 1, 10, and 100µM; 1h) treatment significantly increased the surface and total expression of GluA1 and GluA2 subunits of cultured PFC neurons, and significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but did not increase total protein [4]. LY 379268 (1, 10, 100 and 1000nM; 72h) increased the proliferation of cerebellar progenitor cells in a U-shaped concentration-response curve, with maximum stimulation at concentrations of 1 and 10nM, and decreased stimulation at 100nM, and no effect at 1µM. LY 379268 and fluoxetine have a strong synergistic effect in enhancing cell proliferation and inhibiting cAMP formation [5].
In vivo, LY 379268 (0.25, 1, and 2mg/kg/day; single administration; i.p.) treatment significantly enhanced the expression of BDNF mRNA in the cerebral cortex and hippocampal structures (including the dentate gyrus and pyramidal layer) of mice (CA1-CA3) [6]. LY 379268 (3mg/kg/day; single administration; i.p.) treatment restored the binding level of GABAA-R in the prefrontal cortex and hippocampus (especially CA1 area and DG area) of schizophrenia model mice to normal levels, and showed stronger therapeutic potential than olanzapine [7].
References:
[1] Monn, J A et al. “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.” Journal of medicinal chemistry vol. 42,6 (1999): 1027-40.
[2] Bond, A et al. “LY379268, a potent and selective Group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal, cerebral ischaemia.” Neuroscience letters vol. 273,3 (1999): 191-4.
[3] E F Sharpe, et al. Systemic pre-treatment with a group II mGlu agonist, LY379268, reduces hyperalgesia in vivo. Br J Pharmacol. 2002 Mar;135(5):1255-62.
[4] Wang M J, Li Y C, Snyder M A, et al. Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons[J]. PloS one, 2013, 8(4): e61787.
[5] Matrisciano, F et al. “Synergism between fluoxetine and the mGlu2/3 receptor agonist, LY379268, in an in vitro model for antidepressant drug-induced neurogenesis.” Neuropharmacology vol. 54,2 (2008): 428-37.
[6] Di Liberto V, Bonomo A, Frinchi M, et al. Group II metabotropic glutamate receptor activation by agonist LY379268 treatment increases the expression of brain derived neurotrophic factor in the mouse brain[J]. Neuroscience, 2010, 165(3): 863-873.
[7] Engel, Martin et al. “mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.” Psychopharmacology vol. 233,8 (2016): 1349-59.
LY 379268是一种高选择性、可透过血脑屏障的II组mGlu受体激动剂，对hmGlu2和hmGlu3的EC50值分别为2.69和4.48nM [1]。mGluRs是一种谷氨酸受体，被认为是神经退行性疾病治疗干预的靶点 [2]。LY 379268具有抗氧化和神经保护作用 [3]。
在体外，LY 379268（0.1, 1, 10和100µM; 1h）处理显著增加了培养的PFC神经元GluA1和GluA2亚基的表面和总表达，同时显著增加了细胞外信号调节激酶1/2（ERK1/2）的磷酸化，但没有增加总蛋白 [4]。LY 379268（1, 10, 100和1000nM; 72h）以倒U型浓度-反应曲线增加小脑祖细胞的增殖，在浓度为1和10nM时最大限度地刺激细胞增殖，在100nM时刺激减弱，在1μM时无影响。LY 379268和氟西汀在增强细胞增殖和抑制cAMP形成方面具有强烈的协同作用[5]。
在体内，LY 379268（0.25, 1和2mg/kg/day; 单次给药; i.p.）处理显著增强了小鼠大脑皮层和海马结构（包括齿状回和锥体层）中 BDNF mRNA的表达（CA1-CA3）[6]。LY 379268（3mg/kg/day; 单次给药; i.p.）治疗使精神分裂模型小鼠的前额叶皮质和海马体（特别是CA1区和DG区）中GABAA-R的结合水平恢复到了正常水平，并且显示出比奥氮平更强的治疗潜力 [7]。