Sulfamoylbenzoate Analogues as Putative Treatments for Chronic Neurologic Disease

Sammanfattning

Targeting neuroinflammation, a key factor in the progression of chronic neurological disorders such as Alzheimer’s disease and epilepsy, is essential for discovering effective treatments. Recent studies indicate that Pannexin-1 (Panx-1) channels serve as the primary pathways for ATP release from degenerating and innate immune cells in the brain, triggering neuroinflammation. By blocking it with a potent channel blocker, the chronic activation of Panx-1 channels could be reduced, thereby protecting damaged and dying neurons associated with Alzheimer’s disease and epilepsy. A known channel blocker of the Panx-1 channel is the drug Probenecid, which also acts as an agonist to the TRPV2 channel. Here, we aimed to create analogues of Probenecid to identify a potent channel blocker for either the Panx-1 or the TRPV2 channel. A zebrafish model was used to screen the potency of the created analogues by inducing seizures using pentylenetetrazol, targeting epilepsy in this context. Compound 1002 is the most effective Panx-1 blocker identified in this study, achieving a two-fold decrease in seizure activity at a lower concentration of 70 µM compared to the reference dosage of PBN at 100 µM. Additionally, it showed a twelve-fold increase in seizure inhibition compared to valproic acid at 75 µM, a widely recognized treatment for epilepsy. It was further tested in a mouse model of kainic acid-induced seizures, where it exhibited a similar anti-seizure profile and significantly improved the survival rate of mice after being pretreated with the compound at a dose of 100 mg/kg. Further screening of additional analogues is currently in progress, along with electrophysiology experiments using voltage clamp and site-directed mutagenesis to determine the mechanism of action by which the compound binds and reduces seizures.