Dieter Riddall

Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones.

We report the discovery of a new class of neuroprotective voltage-dependent sodium channel modulators exemplified by (5-(1-benzyl-1H-indazol-3-yl)-1,2,4-oxadiazol-3-yl)methanamine 11 (CFM1178). The compounds were inhibitors of [(14)C]guanidinium ion flux in rat forebrain synaptosomes and displaced binding of the sodium channel ligand [(3)H]BW202W92. 11 and the corresponding N(2)-benzyl isomer, 38 (CFM6058), demonstrated neuroprotective activity in hippocampal slices comparable to sipatrigine. CYP450 enzyme inhibition observed with 11 was reduced with 38. In electrophysiological experiments on dissociated hippocampal neurons, these two compounds caused use- and voltage-dependent block of sodium currents. Sodium channel isoform profiling against Na(v)1.1-1.8 demonstrated that the standard sodium channel blocker lamotrigine had modest activity against Na(v)1.1, while sipatrigine was generally more potent and less selective. 11 and 38 showed potent activity against Na(v)1.6, pointing to pharmacological block of this isoform being consistent with the neuroprotective effect. 38 also showed use dependent block of Na(v)1.6 in HEK cells.

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer thexa0potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3xa0year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

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.

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 Nav channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

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

Page 2944. In Table 1, “[3H]sipatrigine” should read “[3H]BW202W93”. n nPage 2944. In the right column lines 5 and 31, “[3H]sipatrigine” should read “[3H]BW202W93”. n nPage 2945. In Tables 2 and 3, “[3H]sipatrigine” should read “[3H]BW202W93”. n nPage 2946. In Table 4, “[3H]sipatrigine” should read “[3H]BW202W93”. n nPage 2946. In the right column line 9, “[3H]sipatrigine” should read “[3H]BW202W93”.