| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T35135 | ||||
| Target Name | Voltage-gated sodium channel | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | Riluzole | Drug Info | IC50 = 5300 nM | [553274] | |
| Lacosamide | Drug Info | IC50 = 12000 nM | [552804] | ||
| Lidocaine | Drug Info | IC50 = 34000 nM | [553188] | ||
| Action against Disease Model | Lidocaine | We expressed receptors in Xenopus oocytes. Using two-electrode voltage clamp, we measured the effects of lidocaine, QX314 (permanently charged) and benzocaine (permanently uncharged) on Ca(2+)-activated Cl(-)-currents (I(Cl(Ca))), elicited by acetyl-beta-methylcholine bromide (MCh). We also characterized the interaction of lidocaine with [(3)H]-quinuclydinyl benzylate ([(3)H]-QNB) binding to m3 receptors. Antisense-injection was used to determine the role of specific G-protein alpha subunits in mediating the inhibitory effects of LA. Using chimeric receptor constructs weinvestigated which domains of the muscarinic receptors contribute to the binding site for LA.Lidocaine inhibited m3-signalling in a concentration-dependent, reversible, non-competitive manner with anIC(50) of 370 nM, approximately 21 fold higher than the IC(50) (18 nM) reported for m1 receptors | [552253] | Drug Info | |
| Oxcarbazepine | Oxcarbazepine (OXC), one of the newer anti-epileptic drugs, has been demonstrating its efficacy on wide-spectr uM neuropsychiatric disorders. However, the ionic mechanism of OXCactions in neurons remains incompletely understood. With the aid of patch-clamp technology, we first investigated the effects of OXC on ion currents in NG108-15 neuronal cells differentiated with cyclic AMP. We found OXC (0.3-30 microm) caused a reversible reduction in the amplitude of voltage-gated Na+ current (INa). The IC50 value required for the inhibition of INa by OXC was 3.1 microm. OXC (3microm) could shift the steady-state inactivation of INa to a more negative membrane potential by approximately -9 mV with no effect on the slope of the inactivation curve, and produce a significant prolongation in the recovery of INa inactivation. Additionally, OXC was effective in suppressing persistent INa (INa(P)) elicited by long ramp pulses. The blockade of INa by OXC does not simply reducecurrent magnitude, but alters current kinetics. Moreover, OXC could suppress the amplitude of delayed rectifier K+ current (IK(DR)), with no effect on M-type K+ current (IK(M)). In current-clamp configuration, OXC could reduce the amplitude of action potentials and prolong action-potential duration. Furthermore, the simulations, based on hippocampal pyramidal neurons (Pinsky-Rinzel model) and a network of the Hodgkin-Huxley model, were analysed to investigate the effect of OXC on action potentials. Taken together, our results suggest that the synergistic blocking effects on INa and IK(DR) maycontribute to the underlying | [552774] | Drug Info | ||
| Lamotrigine | Lamotrigine is a chemically novel anticonvulsant drug that has been reported to inhibit veratrine-induced neurotransmitter release from cortical slices in vitro. To characterizefurther the mechanism of action of lamotrigine, we have investigated the effects of this drug together with the anticonvulsant drugs phenytoin and carbamazepine on voltage-sensitive sodi uM channels present in N4TG1 mouse neuroblastoma clonal cells. Lamotrigine, phenytoin and carbamazepine produced a tonic inhibition of sodi uM channels with IC50 values of 91, 58 and 140 microM, respectively. At a concentration of 100 microM, all compounds shifted the voltage-dependency of steady-state inactivation toward more negative potentials by 7 to 15 mV, slowed the rate of recovery from inactivation and produced a use-dependent inhibition of sodi uM channels. Our data show that lamotrigine inhibits sodi uM channels in a manner that is similar to that produced by phenytoin and carbamazepine. This inhibition of neuronal activity is consistent with the reduction of glutamate release that was previously reported in neurochemical studies, and it expands our understanding of the mechanism of action of this anticonvulsant drug. | [553224] | Drug Info | ||
| References | |||||
| Ref 553274 | Selective inhibition by riluzole of voltage-dependent sodium channels and catecholamine secretion in adrenal chromaffin cells. Naunyn Schmiedebergs Arch Pharmacol. 1998 May;357(5):526-31. | ||||
| Ref 552804 | Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J Pharmacol Exp Ther. 2008 Jul;326(1):89-99. doi: 10.1124/jpet.107.133413. Epub 2008 Mar 31. | ||||
| Ref 553188 | Veratrine-stimulated phosphoinositide breakdown as an assay for local anesthetic actions at Na+ channels. Anesth Analg. 1995 Sep;81(3):480-5. | ||||
| Ref 552253 | Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics. Br J Pharmacol. 2001 May;133(1):207-16. | ||||
| Ref 552774 | The synergistic inhibitory actions of oxcarbazepine on voltage-gated sodium and potassium currents in differentiated NG108-15 neuronal cells and model neurons. Int J Neuropsychopharmacol. 2008 Aug;11(5):597-610. doi: 10.1017/S1461145707008346. Epub 2008 Jan 10. | ||||
| Ref 553224 | Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther. 1993 Aug;266(2):829-35. | ||||
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