Chine VU 0361737 1161205-04-4 Fabricants

VU 0361737 1161205-04-4

Informations de base

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Poids moléculaire : 262,69 VU 0361737 est un modulateur allostérique positif sélectif (PAM) pour le récepteur mGlu4 avec une CE50 de 240 nM et 110 nM aux récepteurs humains et de rat, respectivement, affiche une faible activité à mGlu5 et Les récepteurs mGlu8, sont inactifs sur les récepteurs mGlu1, mGlu2, mGlu3, mGlu6 et mGlu7, peuvent pénétrer dans le SNC.
Activité biologique VU0361737 est inactif sur les récepteurs mGlu1, mGlu2, mGlu3, mGlu6 et mGlu7 et affiche une faible activité sur les récepteurs mGlu5 et mGlu8. VU0361737 montre une CL élevée in vivo chez le rat, une courte demi-vie (T1/2 20 min) et démontre une exposition cérébrale significative (rapport cerveau-plasma de 4,1).
Protocole (uniquement pour référence) Test de kinase : [2]

Calcium mobilization assays	Human mGluR4/Gqi5/CHO cells (30,000 cells/20 •l/well) are plated in blackwalled, clear-bottomed, TC treated, 384 well plates in DMEM containing 10% dialyzed FBS, 20 mM HEPES, 100 units/ml penicillin/streptomycin, and 1 mM sodium pyruvate. The cells are grown overnight at 37 °C in the presence of 5% CO2. During the day of assay, the medium is replaced with 20 μL of 1 μM Fluo-4, AM prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w/v) pluronic acid F-127 and diluted in Assay Buffer (Hank`s balanced salt solution, 20 mM HEPES and 2.5 mM Probenecid) for 45 minutes at 37 °C. Dye is removed and replaced with 20 μL of Assay Buffer. Test compounds are transferred to daughter plates using an Echo acoustic plate reformatter and then diluted into Assay Buffer. Ca2+ flux is measured using the Functional Drug Screening System 6000. Baseline readings are taken (10 images at 1 Hz, excitation, 470±20 nm, emission, 540±30 nm) and then 20 •l/well test compounds are added using the FDSS`s integrated pipettor. Cells are incubated with compounds for approximately 2.5 minutes and then an EC20 concentration of glutamate is applied; 2 minutes later an EC80 concentration of glutamate is added. For concentration-response curve experiments, compounds are serially diluted 1:3 into 10 point concentration response curves and are transferred to daughter plates using the Echo. Test compounds are again applied and followed by EC20 concentrations of glutamate. For fold shift experiments, compounds are added at 2X their final concentration and then increasing concentrations of glutamate are added in the presence of vehicle or the appropriate concentration of test compound. Curves are fitted using a four point logistical equation using Microsoft XLfit. Subsequent confirmations of concentrationresponse parameters are performed using independent serial dilutions of source compounds and data from multiple days experiments are integrated and fit using a four point logistical equation in GraphPad Prism. Calcium assays are used to assess activity of compounds at mGluRs 1, 4 and 5.

Calcium mobilization assays

Human mGluR4/Gqi5/CHO cells (30,000 cells/20 •l/well) are plated in blackwalled, clear-bottomed, TC treated, 384 well plates in DMEM containing 10% dialyzed FBS, 20 mM HEPES, 100 units/ml penicillin/streptomycin, and 1 mM sodium pyruvate. The cells are grown overnight at 37 °C in the presence of 5% CO2. During the day of assay, the medium is replaced with 20 μL of 1 μM Fluo-4, AM prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w/v) pluronic acid F-127 and diluted in Assay Buffer (Hank`s balanced salt solution, 20 mM HEPES and 2.5 mM Probenecid) for 45 minutes at 37 °C. Dye is removed and replaced with 20 μL of Assay Buffer. Test compounds are transferred to daughter plates using an Echo acoustic plate reformatter and then diluted into Assay Buffer. Ca2+ flux is measured using the Functional Drug Screening System 6000. Baseline readings are taken (10 images at 1 Hz, excitation, 470±20 nm, emission, 540±30 nm) and then 20 •l/well test compounds are added using the FDSS`s integrated pipettor. Cells are incubated with compounds for approximately 2.5 minutes and then an EC20 concentration of glutamate is applied; 2 minutes later an EC80 concentration of glutamate is added. For concentration-response curve experiments, compounds are serially diluted 1:3 into 10 point concentration response curves and are transferred to daughter plates using the Echo. Test compounds are again applied and followed by EC20 concentrations of glutamate. For fold shift experiments, compounds are added at 2X their final concentration and then increasing concentrations of glutamate are added in the presence of vehicle or the appropriate concentration of test compound. Curves are fitted using a four point logistical equation using Microsoft XLfit. Subsequent confirmations of concentrationresponse parameters are performed using independent serial dilutions of source compounds and data from multiple days experiments are integrated and fit using a four point logistical equation in GraphPad Prism. Calcium assays are used to assess activity of compounds at mGluRs 1, 4 and 5.

Étude animale : [1]

Animal Models	Sprague-Dawley rats
Formulation	10% Tween-80
Dosages	10 mg/kg
Administration	ip

Conversion de différents animaux modèles sur la base de la BSA (valeur basée sur les données des lignes directrices provisoires de la FDA)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

Par exemple, pour modifier la dose de resvératrol utilisée pour une souris (22,4 mg/kg) à une dose basée sur la BSA pour un rat, multiplier 22,4 mg/kg par le facteur Km pour une souris puis diviser par le facteur Km pour un rat. Ce calcul donne une dose équivalente chez le rat pour le resvératrol de 11,2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Informations chimiques

Molecular Weight (MW)	262.69
Formula	C13H11ClN2O2
CAS No.	1161205-04-4

Storage	3 years -20℃Powder
Storage	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	53 mg/mL (201.75 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.