VU0409551 (JNJ-46778212) is a potent and selective biased positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGlu5 PAM; EC50=260nM)[1-2]. VU0409551 selectively potentiates mGlu5-mediated Gaq signaling without modulating NMDAR currents. VU0409551 is used in research related to schizophrenia, Huntington's disease, Phelan-McDermid syndrome, and autism spectrum disorders[3-4].
In vitro, HEK293A cells expressing low levels of mGlu5 (HEK293A-mGlu5-low) were treated with VU0409551 (0.1nM-0.1µM) for 1 hour. VU0409551 induced calcium mobilization, mGlu5 accumulation, and ERK1/2 phosphorylation[5]. HEK293A cells expressing rat mGlu5 were treated with VU0409551 (0.1nM-10µM) for 5-60 minute, followed by a challenge with a maximal concentration of glutamate (100µM) or DHPG (30µM). VU0409551 potentiated the desensitization of DHPG-induced, mGlu5-mediated intracellular calcium mobilization[6].
In vivo, BACHD mouse models of Huntington's disease, aged 8-10 months, received daily intraperitoneal injections of VU0409551 (3mg/kg) for 8 days. VU0409551 ameliorated memory deficits in BACHD mice, increased mGluR5 expression at the plasma membrane, elevated the expression levels of synaptic plasticity-related genes (such as BDNF, Arc/Arg3.1, c-Fos, Syntaxin 1A, PSD-95), and increased dendritic spine density, maturity, and the number of presynaptic terminals[7]. Rats were treated with VU0409551 (1mg/kg to 450mg/kg; oral administration) for 7 days. VU0409551 significantly reversed amphetamine-induced hyperactivity and enhanced cognitive function in mice[8].
References:
[1] Hellyer SD, Sengmany K, Keller AN, et al. Probe dependence and biased potentiation of metabotropic glutamate receptor 5 is mediated by differential ligand interactions in the common allosteric binding site. Biochem Pharmacol. 2020 Jul;177:114013.
[2] Balu DT, Li Y, Takagi S, et al. An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology. 2016 Jul;41(8):2052-61.
[3] Brown J, Iacovelli L, Di Cicco G, et al. The comparative effects of mGlu5 receptor positive allosteric modulators VU0409551 and VU0360172 on cognitive deficits and signalling in the sub-chronic PCP rat model for schizophrenia. Neuropharmacology. 2022 May 1;208:108982.
[4] Brown J, Grayson B, Neill JC, et al. Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172. Cells. 2023 Mar 16;12(6):919.
[5] Sengmany K, Singh J, Stewart GD, et al. Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery. Neuropharmacology. 2017 Mar 15;115:60-72.
[6] Hellyer SD, Albold S, Sengmany K, et al. Metabotropic glutamate receptor 5 (mGlu5 )-positive allosteric modulators differentially induce or potentiate desensitization of mGlu5 signaling in recombinant cells and neurons. J Neurochem. 2019 Nov;151(3):301-315.
[7] Doria JG, de Souza JM, Silva FR, et al. The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease. J Neurochem. 2018 Oct;147(2):222-239.
[8] Conde-Ceide S, Martínez-Viturro CM, Alcázar J, et al. Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia. ACS Med Chem Lett. 2015 May 20;6(6):716-20.
VU0409551 (JNJ-46778212)是一种强效且选择性的偏向性代谢型谷氨酸受体5亚型正变构调节剂（mGlu5 PAM；EC50=260nM）[1-2]。VU0409551可选择性增强mGlu5与Gaq介导的信号传导而不调节NMDAR电流。VU0409551可用于精神分裂症、亨廷顿病、Phelan-McDermid综合征和自闭症谱系障碍的相关研究[3-4]。
在体外，VU0409551（0.1nM-0.1μM）处理低水平表达mGlu5的HEK293A细胞（HEK293A-mGlu5-low）1小时。VU0409551可诱导钙离子、mGlu5的累积和ERK1/2磷酸化[5]。VU0409551（0.1nM-10μM）处理表达大鼠mGlu5的HEK293A细胞5-60分钟，随后以最大浓度的谷氨酸盐（100μM）或DHPG（30μM）进行挑战。VU0409551能增强DHPG诱导的mGlu5介导的细胞内钙动员脱敏[6]。
在体内，VU0409551（3mg/kg）每日一次腹腔注射，用于处理8至10月龄的BACHD亨廷顿病模型小鼠，持续8天。VU0409551改善了BACHD小鼠的记忆缺陷，并增加了mGluR5在细胞质膜的表达，提高了与突触可塑性相关基因（如BDNF、Arc/Arg3.1、c-Fos、Syntaxin 1A、PSD-95）的表达水平，同时增加了树突棘的密度、成熟度以及突触前终末的数量[7]。VU0409551（1mg/kg至450mg/kg；口服）用于处理大鼠7天。VU0409551显著逆转了安非他明诱导的多动症，增强了小鼠的认知功能[8]。