1623101-11-0

Basic information

• Product Name: VU0483605
• Synonyms: VU0483605;2-Chloro-N-[3-chloro-4-(4-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]nicotinamide;3-Chloro-N-(3-chloro-4-(4-chloro-1,3-dioxoisoindolin-2-yl)phenyl)picolinamide
• CAS NO: 1623101-11-0
• Molecular Formula: C20H10Cl3N3O3
• Molecular Weight: 446.6707
• Mol File: 1623101-11-0.mol
• Article Data: 1

Chemical Properties

• Appearance: /
• Density: 1.625±0.06 g/cm3(Predicted)
• Solubility: ≤20mg/ml in DMSO;20mg/ml in dimethyl formamide
• PKA: 9.39±0.70(Predicted)
• CAS DataBase Reference: VU0483605(CAS DataBase Reference)
• NIST Chemistry Reference: VU0483605(1623101-11-0)
• EPA Substance Registry System: VU0483605(1623101-11-0)

Safety Data

• Hazardous Substances Data: 1623101-11-0(Hazardous Substances Data)

Usage

Uses

VU 0483605 is a positive allosteric modulator of metabotropic glutamate receptors (mGluRs) that preferentially binds mGlu1 over mGlu4 (1,2). VU 0483605 is a mGlu1 antagonist and has potential therapeutic properties for treating schizophrenia.

Biological Activity

vu0483605 is a selective positive allosteric modulator (pam) of mglur1 [1].the metabotropic glutamate receptors (mglurs), members of g-protein-coupled receptors, have been involved in a variety of functions in the central and peripheral nervous systems, such as learning, memory, anxiety, and the perception of pain. the mglurs exist in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, the cerebral cortex, as well as other parts of the brain and in peripheral tissues. mice deficient in mglur1 showed severe motor coordination and spatial learning deficient [2].vu0483605 is a selective positive allosteric modulator (pam) of mglur1. vu0483605 displayed ec50 values of 0.39 and 0.36 μm at human and rat mglur1 receptors, respectively. vu0483605 showed no activity against mglu4 pam with the ec50 of >10 μm. vu0483605 potentiated the response to glutamate in cells stably expressing mglu1 and partially restored the reduction in glutamate-mediated calcium signaling in a mutant cell model of schizophrenia [1].

references

[1] cho h p, garcia-barrantes p m, brogan j t, et al. chemical modulation of mutant mglu1 receptors derived from deleterious grm1 mutations found in schizophrenics[j]. acs chemical biology, 2014, 9(10): 2334-2346.[2] conquet f, bashir z i, davies c h, et al. motor deficit and impairment of synaptic plasticity in mice lacking mglur1[j]. nature, 1994, 372(6503): 237.

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Relevant articles and documents

Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics

(Figure Presented) Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu1), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu1 mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu1 receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu1 positive allosteric modulators (PAM) tool compounds active at human mGlu1, we optimized a known mGlu4 PAM/mGlu1 NAM chemotype into a series of potent and selective mGlu1 PAMs by virtue of a double "molecular switch". Employing mGlu1 PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu1 receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu1 PAM. However, in wild type animals, mGlu1 negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu1 PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.