化合物信息

Description

Neurological Disease

Description

Carbamazepine (Carbatrol) is a sodium channel blocker with IC50 of 131 μM in rat brain synaptosomes.

Targets

IC₅₀

In Vitro

Carbamazepine inhibits the binding of [³H]batrachotoxinin A 20-α-benzoate (BTX-B) to a receptor site of voltage-sensitive sodium channel with IC50 of 131 μM, to decrease the activation of sodium channel ion flux in rat brain synaptosomes. Carbamazepine reduces receptor affinity due to an increased rate of ligand dissociation from the receptor-ligand complex, without altering maximal binding capacity from the scatchard analysis of BTX-B binding to synaptosome, suggesting an indirect allosteric mechanism for anticonvulsant inhibition of BTX-B binding. Carbamazepine does not alter basal ¹²⁵I-labeled scorpion toxin binding to synaptosomes in the absence of batrachotoxin, but when batrachotoxin (1.25 μM) added, Carbamazepine inhibits the batrachotoxin-dependent increase in scorpion toxin binding in a concentration-dependent manner with IC50 of 260 μM mediated at the alkaloid toxin binding site, none of which affects [³H]saxitoxin binding. ^[1]

In Vivo

Carbamazepine at 25 mg/kg significantly increases extracellular levels of striatal and hippocampal dopamine (DA), 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in a dose dependent manner, while Carbamazepine at 50 mg/kg significantly decreases total levels of striatal DA and DOPA as well as hippocampal HVA, but has no effect on total levels of striatal DOPAC and HVA nor on hippocampal DA, DOPA and DOPAC. ^[2] Intraperitoneal administration of Carbamazepine （~100 mg/kg）to rats produces significant increases in the cerebral cortical concentrations of neuroactive steroids and neuroactive steroids in plasma in a dose and time dependent maner with DHEA formed as a result of side chain cleavage of pregnenolone not affected. ^[3]

Clinical Trials

Phase III has been completed in the study of comparing the efficacy and safety of Zonisamide and Carbamazepine as monotherapy, in newly diagnosed partial epilepsy.

Features

Carbamazepine is a most frequently prescribed first-line drug for the treatment of partial and generalized tonic-clonic epileptic seizures.

[3H]BTX-B binding assay

[³H]BTX-B binding is studied by incubating synaptosomes (1.10 mg/mL) for 30 minutes at 36 °C in the standard incubation medium containing 25 mM KCl and 105 mM choline chloride plus [³H]BTX-B (10 nM), tetrodotoxin (1 μM), scorpion toxin (0.3 or 2 μM), BSA (1 mg/mL), and varying concentrations of Carbamazepine. Nonspecific binding of [³H]BTX-B is determined in the presence of 0.3 mM veratridine. Binding reactions are initiated by the addition of 25 μL of the synaptosomal suspension to 175 μL of the reaction mixture. Samples are rapidly mixed and, following incubation (10 minutes), the reaction is stopped by the addition of 3 mL of ice-cold wash medium consisting of choline chloride (163 mM), 5 mM Hepes-Tris (pH 7.4), CaCl₂ (1.8 mM), MgSO₄ (0.8 mM), and BSA (1 mg/mL). The synaptosomes are immediately collected on glassfiber filters under vacuum and washed three times with 3 mL of wash medium. Filters containing trapped synaptosomes are suspended in liquid scintillation fluid, and ³H bound is determined in a liquid scintifiation spectrometer. The IC50 determination is calculated by log-probit analysis according to the method of Finney.

Animal Models

Male Wistar rats

Formulation

Dissolved in saline/DMSO (50/50 vol/vol)

Doses

~100 mg/kg

Administration

Injected intraperitoneally (i.p.)