Sulfamoylbenzoate Analogues as Putative Treatments for Chronic Neurologic Disease
(2025) KEMR30 20251Department of Chemistry
- Abstract
- 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... (More)
- 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. (Less)
- Popular Abstract (Swedish)
- Alzheimers och epilepsi är två sjukdomar som tillhör gruppen kronisk neurologiska sjukdomar som påverkar det centrala nervsystemet. Många läkemedelsstudier har gjorts på läkemedel som kan ändra på den faktiska sjukdomspatologin men än så länge utan framgång, endast läkemedel som tar hand om symptom finns idag på marknaden. Denna studie har som mål att hitta en kandidat till ett läkemedel som kan ändra den faktiska orsaken till att dessa sjukdomar uppstår. Detta projekt utgick från ett känt läkemedel, Probenecid, som idag används mot gikt, en ledinflammation som uppkommer av att det bildats kristaller av urinsyra i leden på patienten. Genom att syntetisera analoger, vilket inom läkemedelsindustrin betyder att man tar en existerande struktur... (More)
- Alzheimers och epilepsi är två sjukdomar som tillhör gruppen kronisk neurologiska sjukdomar som påverkar det centrala nervsystemet. Många läkemedelsstudier har gjorts på läkemedel som kan ändra på den faktiska sjukdomspatologin men än så länge utan framgång, endast läkemedel som tar hand om symptom finns idag på marknaden. Denna studie har som mål att hitta en kandidat till ett läkemedel som kan ändra den faktiska orsaken till att dessa sjukdomar uppstår. Detta projekt utgick från ett känt läkemedel, Probenecid, som idag används mot gikt, en ledinflammation som uppkommer av att det bildats kristaller av urinsyra i leden på patienten. Genom att syntetisera analoger, vilket inom läkemedelsindustrin betyder att man tar en existerande struktur och med hjäp av kemi bygger den, är det möjligt att skapa starkare bindning till ett bestämt målprotein, exempelvis en jonkanal eller ett enzym som finns i kroppen. I detta fall var målet en jonkanal vid namn Pannexin-1 som finns i hjärnan, främst i neuroner och gliaceller. Neuroner är hjärnans kommunikatörer, som tar emot, bearbetar och skickar information runt om i kroppen så att vi kan tänka, känna, röra oss och reagera på omvärlden. 22 analoger av Probenecid syntetiserades i denna studie och testades i två djurmodeller: en zebrafiskmodell och en musmodell, där djuren har Pannexin-1 kanaler i hjärnan. Det som specifikt testades var huruvida analogerna som skapats kunde reducera epilepsianfall. Detta testades genom att man gav djuren en molekyl som man vet inducerar kraftiga anfall, sedan tillförde man analogerna för att se om de reducerade anfallen. En analog, reducerade anfallen så pass bra att ett provisoriskt patent skickades in. Detta är en lovande start som kan bana vägen för nya framsteg inom detta område, men som fortfarande kräver mer forskning och optimering. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9195049
- author
- Lund, Hannah LU
- supervisor
- organization
- course
- KEMR30 20251
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- organic chemistry, Alzheimer, panx-1 channel, TRPV2 channel
- language
- English
- id
- 9195049
- date added to LUP
- 2025-07-02 09:12:34
- date last changed
- 2025-07-02 09:12:34
@misc{9195049,
abstract = {{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.}},
author = {{Lund, Hannah}},
language = {{eng}},
note = {{Student Paper}},
title = {{Sulfamoylbenzoate Analogues as Putative Treatments for Chronic Neurologic Disease}},
year = {{2025}},
}