VU 0357121

• CAT Number: I003545
• CAS Number: 433967-28-3
• Molecular Formula: C17H17F2NO2
• Molecular Weight: 305.33
• Purity: ≥95%
• Synonyms: 4-butoxy-N-(2,4-difluorophenyl)benzamide
• Target: Neuronal Signaling
• Solubility: DMSO 60 mg/mL; Water <1 mg/mL
• Storage: 3 years -20C powder
• IC50: 33 nM(EC50)
• InChI: InChI=1S/C17H17F2NO2/c1-2-3-10-22-14-7-4-12(5-8-14)17(21)20-16-9-6-13(18)11-15(16)19/h4-9,11H,2-3,10H2,1H3,(H,20,21)
• InChIKey: AHCYOTLTLQTPSU-UHFFFAOYSA-N
• SMILES: CCCCOC1=CC=C(C=C1)C(=O)NC2=C(C=C(C=C2)F)F

VU0357121 (Cat No.: I003545) is a selective positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGluR5), a receptor involved in synaptic plasticity, learning, memory, and various neurological disorders. By enhancing the receptor’s response to glutamate without directly activating it, VU0357121 allows for fine-tuned modulation of mGluR5 signaling. It is primarily used in neuroscience research to investigate the therapeutic potential of mGluR5 modulation in conditions such as schizophrenia, anxiety, and fragile X syndrome, contributing to the development of targeted CNS therapies.

Reference

[1]. Hammond, Alexis S.; Rodriguez, Alice L.; Townsend, Steven D. et al. Discovery of a Novel Chemical Class of mGlu5 Allosteric Ligands with Distinct Modes of Pharmacology. ACS Chemical Neuroscience (2010), 1(10), 702-716.
Abstract
We previously discovered a positive allosteric modulator (PAM) of the metabotropic glutamate receptor subtype 5 (mGlu(5)) termed 4 N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) that elicits receptor activation through a novel allosteric site on mGlu(5), distinct from the classical mGlu(5) negative allosteric modulator (NAM) MPEP allosteric site. However, a shallow structure-activity relationship (SAR), poor physiochemical properties, and weak PAM activity at rat mGlu(5) limited the utility of CPPHA to explore allosteric activation of mGlu(5) at a non-MPEP site. Thus, we performed a functional high-throughput screen (HTS) and identified a novel mGlu(5) PAM benzamide scaffold, exemplified by VU0001850 (EC(50) = 1.3 μM, 106% Glu(max)) and VU0040237 (EC(50) = 350 nM, 84% Glu Max). An iterative parallel synthesis approach delivered 22 analogues, optimized mGlu(5) PAM activity to afford VU0357121 (EC(50) = 33 nM, 92% Glu(max)), and also revealed the first non-MPEP site neutral allosteric ligand (VU0365396). Like CPPHA, PAMs within this class do not appear to bind at the MPEP allosteric site based on radioligand binding studies. Moreover, mutagenesis studies indicate that VU0357121 and related analogues bind to a yet uncharacterized allosteric site on mGlu(5), distinct from CPPHA, yet share a functional interaction with the MPEP site.