Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones
| Autor: | Dieter Riddall, Paul J. Gane, Cristina Garcia Posada, Barrie Lancaster, Lisa Clutterbuck, Cristina Visintin, David L. Selwood, John Garthwaite |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Male
Indazoles Quantitative Structure-Activity Relationship Lamotrigine Hippocampal formation Neuroprotection Hippocampus Sodium Channels Sodium channel blocker Cytochrome P-450 Enzyme System Drug Discovery medicine Animals Cytochrome P-450 Enzyme Inhibitors Protein Isoforms Rats Wistar Neurons Chemistry Sodium channel Electrophysiological Phenomena Rats Electrophysiology medicine.anatomical_structure Neuroprotective Agents Biochemistry Drug Design Forebrain Biophysics Molecular Medicine Neuron medicine.drug Sodium Channel Blockers |
| Zdroj: | Journal of medicinal chemistry. 52(9) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|