VU 0361737 (VU0361737; VU-0361737) is a novel, brain-penetrable and selective positive allosteric modulator (PAM) for mGlu4 receptor with important biological activity. It inhibits mGlu4 receptor with an EC50 of 240 nM and 110 nM at human and rat receptors, respectively. It exhibits little activity against mGlu5/8 receptors.
Physicochemical Properties
| Molecular Formula | C13H11CLN2O2 | |
| Molecular Weight | 262.69 | |
| Exact Mass | 262.05 | |
| CAS # | 1161205-04-4 | |
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| PubChem CID | 44191096 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 329.8±37.0 °C at 760 mmHg | |
| Flash Point | 153.3±26.5 °C | |
| Vapour Pressure | 0.0±0.7 mmHg at 25°C | |
| Index of Refraction | 1.633 | |
| LogP | 2.44 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 18 | |
| Complexity | 288 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | ARYUXFNGXHNNDM-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C13H11ClN2O2/c1-18-12-8-9(5-6-10(12)14)16-13(17)11-4-2-3-7-15-11/h2-8H,1H3,(H,16,17) | |
| Chemical Name | N-(4-chloro-3-methoxyphenyl)pyridine-2-carboxamide | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Metabotropic glutamate receptor 4 (mGluR4) (EC50 = 1.8 μM in calcium flux assay; EC50 = 2.3 μM in cAMP inhibition assay) [1] |
| ln Vitro |
VU0361737 exhibits inactive behavior at mGlu1, mGlu2, mGlu3, mGlu6 and mGlu7 receptors and weak activity at mGlu5 and mGlu8 receptors[1]. In human neuroblastoma SH-SY5Y cells, VU0361737 (1–10 μM) partially attenuates the effects of doxorubicin and staurosporine on cell death[3]. VU 0361737 acts as a positive allosteric modulator (PAM) of mGluR4, enhancing the agonist activity of glutamate at the receptor. In calcium flux assays using HEK293 cells expressing human mGluR4, it exhibited an EC50 of 1.8 μM when co-administered with 10 μM glutamate (a submaximal concentration) [1] - In cAMP inhibition assays, VU 0361737 (0.1–30 μM) dose-dependently enhanced glutamate-induced inhibition of forskolin-stimulated cAMP accumulation, with an EC50 of 2.3 μM [1] - The compound showed high selectivity for mGluR4, with no significant activity (EC50 > 30 μM) against other mGluR subtypes (mGluR1, mGluR2, mGluR3, mGluR5, mGluR6, mGluR7, mGluR8) in calcium flux or cAMP assays [1] |
| ln Vivo | After intraperitoneal administration (rat 10 mg/kg), VU0361737 shows terminal elimination half-lives (rat 1.9 h) because of high plasma clearance (894 mL/min/kg)[1]. |
| Enzyme Assay |
Calcium flux assay: HEK293 cells stably expressing human mGluR4 were seeded in 96-well plates and loaded with a fluorescent calcium indicator for 1 hour at 37°C. Serial dilutions of VU 0361737 (0.01–30 μM) were prepared and mixed with 10 μM glutamate (submaximal agonist concentration). The mixture was added to the loaded cells, and fluorescence intensity was measured continuously for 30 seconds to detect calcium mobilization. EC50 values were calculated by nonlinear regression analysis of the concentration-response curves [1] - cAMP inhibition assay: HEK293 cells expressing mGluR4 were seeded in 24-well plates and preincubated with 10 μM forskolin for 15 minutes. VU 0361737 (0.1–30 μM) and 10 μM glutamate were added, and the cells were incubated for 30 minutes at 37°C. The reaction was terminated by lysing the cells, and intracellular cAMP levels were quantified using a competitive ELISA kit. EC50 values were determined based on the dose-dependent enhancement of glutamate-mediated cAMP inhibition [1] |
| Animal Protocol |
Animal/Disease Models: Male SD (Sprague-Dawley) rats (225- 250 g)[1] Doses: 10 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: intraperitoneal (ip)injection Experimental Results: T1/2 (1.9 h). |
| ADME/Pharmacokinetics |
VU 0361737 demonstrated central nervous system (CNS) penetration in rats. After oral administration of 30 mg/kg, the brain concentration reached 1.2 μM at 1 hour post-dosing, with a brain-to-plasma concentration ratio of 0.8 [1] - The oral bioavailability of VU 0361737 in rats was 35%, with a maximum plasma concentration (Cmax) of 1.5 μM and a plasma half-life (t1/2) of 2.7 hours [1] |
| References |
[1]. Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J Med Chem. 2009 Jul 23;52(14):4115-8. [2]. Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats. J Med Ch. [3]. Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation. Neurochem Int. 2015 Sep;88:124. |
| Additional Infomation |
VU 0361737 belongs to the heterobiarylamide class of compounds, designed as a centrally penetrant PAM of mGluR4 [1] - Its mechanism of action involves binding to the allosteric site of mGluR4, which potentiates the receptor’s response to endogenous glutamate, thereby modulating glutamate neurotransmission in the CNS [1] - The high selectivity for mGluR4 and CNS penetration make it a potential chemical tool for studying mGluR4-mediated physiological processes and therapeutic applications in neurological disorders [1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 2 mg/mL (7.61 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8068 mL | 19.0338 mL | 38.0677 mL | |
| 5 mM | 0.7614 mL | 3.8068 mL | 7.6135 mL | |
| 10 mM | 0.3807 mL | 1.9034 mL | 3.8068 mL |