product name CTEP (RO4956371)
Description: CTEP (also known as RO4956371) is a novel, potent, long-acting, orally bioavailable allosteric antagonist of mGlu5 receptor with IC50 of 2.2 nM, it shows >1000-fold selectivity over other mGlu receptors. CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors.
References: J Pharmacol Exp Ther. 2011 Nov;339(2):474-86; Neuron. 2012 Apr 12;74(1):49-56.
391.77
Formula
C19H13ClF3N3O
CAS No.
871362-31-1
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 78 mg/mL (199.1 mM)
Water: <1 mg/mL
Ethanol: 10 mg/mL (25.5 mM)
Solubility (In vivo)
30% propylene glycol, 5% Tween 80, 65% D5W: 6 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19423320
| In Vitro |
In vitro activity: CTEP inhibits quisqualate-induced Ca2+ mobilization with an IC50 of 11.4 nM and [3H]IP accumulation with an IC50 of 6.4 nM in HEK293 cells stably expressing human mGlu5. CTEP inhibits the constitutive activity of human mGlu5 by approximately 50% with an IC50 of 40.1 nM in HEK293 cells stably expressing human mGlu5. Kinase Assay: For all filtration radioligand binding assays, membrane preparations expressing the target receptors or receptor combinations are resuspended in radioligand binding buffer (15 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, 1.25 mM CaCl2, and 1.25 mM MgCl2, pH 7.4), and the membrane suspension is mixed with the appropriate concentrations of radioligand and nonlabeled drugs in 96-well plates in a total volume of 200 μL and incubated for 60 min at the appropriate temperature. At the end of the incubation, membranes are filtered onto Whatman Unifilter preincubated with 0.1% polyethyleneimine in wash buffer (50 mM Tris-HCl, pH 7.4) with a Filtermate 196 harvester and washed three times with ice-cold wash buffer. Radioactivity captured on the filter is quantified on a Topcount microplate scintillation counter with quenching correction after the addition of 45 μL of MicroScint 40 per well and shaking for 20 min. The concentration of membranes and incubation time is determined for each assay in pilot experiments. Cell Assay: In HEK293 cells expressing mGlu5, CTEP inhibits quisqualate-induced Ca2+ mobilization and inositol phosphate accumulation with IC50 value of 11.4nM and 6.4nM, respectively. In addition, it shows an IC50 value of 40.1nM in the IP accumulation assay, demonstrating its inverse agonist activity. CTEP is proved to be a highly selective inhibitor of mGlu5. It shows no significant activity against mGlu1, mGlu2, mGlu3, mGlu4, mGlu6, mGlu7 or mGlu8 at concentration up to 10μM. |
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| In Vivo | CTEP is significantly active at doses of 0.1 mg/kg and 0.3 mg/kg in treatment of anxiety in mouse. CTEP significantly increases drinking time at doses of 0.3 mg/kg and 1.0 mg/kg in the Vogel conflict drinking test in rat, whereas it has no effect at lower doses. The half-life of CTEP (oral) is 18 h, and the B/P ratio based on total drug concentrations in plasma and whole brain homogenates is 2.6 in mice. After single oral doses of 4.5 and 8.7 mg/kg CTEP formulated as microsuspension in a saline/Tween vehicle administrated to adult C57BL/6 mice is rapidly absorbed and achieves close to maximal exposure after approximately 30 min. Chronic administration in adult mice with a dose of 2 mg/kg p.o. every 48 h for 2 months reaches a minimal CTEP brain exposure of 240 ng/g. CTEP fully displaces [3H]ABP688 in mouse brain regions known to express mGlu5, and 50% displacement is achieved with doses producing an average compound concentration of 77.5 ng/g measured in whole brain homogenate. CTEP (2 mg/kg p.o. bid) achieves uninterrupted mGlu5 occupancy per 48 hours in mice. CTEP (2 mg/kg p.o.) treatment corrects elevated hippocampal long-term depression, excessive protein synthesis, and audiogenic seizures in the Fmr1 knockout mouse. |
| Animal model | Male Sprague-Dawley rats |
| Formulation & Dosage | Dissolved in 0.9% NaCl (w/v) and 0.3% Tween 80 (v/v) solution; 1 mg/kg; oral gavage |
| References | J Pharmacol Exp Ther. 2011 Nov;339(2):474-86; Neuron. 2012 Apr 12;74(1):49-56. |
