Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis

[Image: see text] A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Na(v) channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis

New medical use of triazine derivatives

Compounds of formula (I) especially where R1 is an optionally substituted alkyl, aralkyl or heterocyclyl-alkyl group, are shown to have activity as sodium channel blockers or as antifolates. Some novel compounds where R1 is an aralkyl or heterocyclyl-alkyl are disclosed

A novel drug binding site on voltage-gated sodium channels in rat brain

The effectiveness of several antiepileptic, analgesic, and neuroprotective drugs is attributable to state-dependent inhibition of voltage-gated sodium channels. To help characterize their site and mode of action on sodium channels, a member of the lamotrigine family, R-(�)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)- pyrimidine (BW202W92), was radiolabeled and used as a binding ligand in rat forebrain synaptosomes. Although the level of specific [3H]BW202W92 binding in a standard incubation medium was relatively poor, low concentrations of tetrodotoxin (EC50 � 2–3 nM) greatly enhanced the binding, apparently by increasing the affinity of the binding sites. Tetrodotoxin-dependent binding was stereoselective (the less active enantiomer, S-(�)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)- pyrimidine (BW203W92), was up to 30-fold less potent, depending on conditions) and was extremely sensitive to inhibition by raised K� concentration (IC50 � 5.9 mM), an effect that was ascribed to changes in membrane potential. In addition, the binding was inhibited by sodium channel neurotoxins acting on sites 3 and 4, but it was resistant to batrachotoxin (site 2) and brevetoxin (site 5). Several drugs acting on sodium channels displaced tetrodotoxin-dependent [3H]BW202W92 binding, and most of those tested showed different affinities under depolarized (100 mM K�) and polarized (1 mM K�) conditions. In a subset of compounds for which data were available, binding affinity in depolarized synaptosomes correlated well with apparent affinity for the inactivated state of sodium channels. The [3H]BW202W92 binding site is novel and is likely to represent a pharmacologically important site of action of drugs on voltage-gated sodium channels in the brain

Cyclic triazo and diazo sodium channel blockers

Compounds of general structure in which X and Y are each N or C with at least one of X and Y being N; Z is a single bond or an optionally substituted linking group R1 is hydrogen or a substituent group; R2 is amino or a substituent group; N* is amino when RI is hydrogen or =NH when R1 is a substituent group; or N* is a group NRaRb where Ra and Rb are independently H or an alkyl group; or N* is an optionally substituted piperazinyl ring; and A is an optionally substituted heterocyclic or carbocyclic ring system which may be linked to the triazo/diazo ring through R2 to form a fused multicyclic ring; are indicated as suitable for treatment of disorders in mammals that are susceptible to sodium channel blockers and antifolates, and particularly disorders such epilepsy, multiple sclerosis, glaucoma and uevitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia and trigeminal autonomic cephalalgias; for treatment of mammalian cancers; and for treatment of malaria

Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis

A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Na_v channels. Metabolically stable analogue <b>6</b> was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis