Mavoglurant (AFQ056) is a structurally selective, non-competitive, orally active antagonist of the metabotropic glutamate receptor 5 (mGluR5), with an IC50 value of 30nM [1]. mGluR5 is a transmembrane (TM) G protein-coupled receptor that is highly expressed in the cerebral cortex and hippocampus regions and plays a dominant role in brain diseases related to cognitive dysfunction [2]. Mavoglurant can be used to study fragile X syndrome (FXS) and Parkinson's disease-induced motor disorders caused by levodopa [3-4].
In vitro, treatment with Mavoglurant (1mM; 3 and 8 days) significantly reduced the transcriptional level of FMR1 in the FXS lymphoblastoid cell line [5]. Treatment with Mavoglurant (0.0625, 0.25, 0.5, 1.0 and 2.5μM; 0-75min) significantly reduced the dendritic APP expression in Fmr1 KO primary neurons, and decreased the length of dendritic spines and the density of immature dendritic spines (ciliary protrusions) [6].
In vivo, Mavoglurant (3.1mg/kg or 9.4mg/kg; i.v. or oral; single dose) treatment achieved the maximum concentration of Mavoglurant in rat plasma and brain 0.25 hours after oral administration, and reached the maximum concentration 0.08 hours after intravenous administration [1]. Mavoglurant (1, 3 and 10mg/kg/day; i.p.; single dose) treatment of mice with auditory epilepsy seizures effectively reduced the seizure and running symptoms of Fmr1 KO mice at doses of 3 and 10mg/kg, but was ineffective at 1mg/kg [6].
References:
[1] Vranesic I, Ofner S, Flor P J, et al. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization[J]. Bioorganic & Medicinal Chemistry, 2014, 22(21): 5790-5803.
[2] Kumar A, Dhull D K, Mishra P S. Therapeutic potential of mGluR5 targeting in Alzheimer's disease[J]. Frontiers in neuroscience, 2015, 9: 215.
[3] Petrov D, Pedros I, de Lemos ML, et al. Mavoglurant as a treatment for Parkinson's disease. Expert Opin Investig Drugs. 2014;23(8):1165-1179.
[4] Jacquemont S, Curie A, des Portes V, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3(64):64ra1.
[5] Tabolacci E, Pirozzi F, Gomez-Mancilla B, et al. The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro[J]. BMC medical genetics, 2012, 13(1): 13.
[6] Westmark PR, Dekundy A, Gravius A, Danysz W, Westmark CJ. Rescue of Fmr1KO phenotypes with mGluR5 inhibitors: MRZ-8456 versus AFQ-056. Neurobiol Dis. 2018;119:190-198.
Mavoglurant (AFQ056)是一种结构选择性的、非竞争性的、具有口服活性的代谢型谷氨酸受体5（mGluR5）拮抗剂，IC50值为30nM [1]。mGluR5是一种跨膜（TM）G蛋白偶联受体，在大脑皮层和海马体区域表达较高，在认知功能障碍相关的脑部疾病中占主导地位 [2]。Mavoglurant可用于研究脆性X综合征（FXS）和帕金森氏症中左旋多巴引起的运动障碍 [3-4]。
在体外，Mavoglurant（1mM; 3和8 days）处理显著下降了FXS淋巴母细胞系中FMR1的转录水平 [5]。Mavoglurant（0.0625、0.25、0.5、1.0和2.5μM; 0-75min）处理显著降低了Fmr1 KO原代神经元中树突性APP表达，并减少了树突棘的长度和未成熟树突棘（纤毛状突起）的密度 [6]。
在体内，Mavoglurant（3.1mg/kg or 9.4mg/kg; i.v. or oral; single dose）治疗通过口服给药后0.25小时Mavoglurant在大鼠血浆和大脑中达到了最大浓度，静脉给药后在0.08小时达到最大浓度 [1]。Mavoglurant（1、3和10mg/kg/day; i.p. ; single dose）治疗听源性癫痫发作小鼠，在剂量为3和10mg/kg时能有效减轻Fmr1 KO小鼠的癫痫发作和狂奔症状，但在1mg/kg剂量下无效[6]。