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Related Concept Videos

Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein01:20

Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein

Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
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Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:29

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Antiepileptic Drugs: GABAergic Pathway Potentiators01:18

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γ-aminobutyric acid or GABA, plays a pivotal role as an inhibitory neurotransmitter in the brain. GABA pathway potentiators, also known as GABAergic drugs, are a class of pharmaceutical agents designed to enhance the functioning of the GABAergic system. These medications primarily treat epilepsy, a neurological disorder characterized by recurrent seizures.
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Quantitative Measurement of &#947;-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
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Published on: January 25, 2018

Aminothiazoles as γ-secretase modulators.

Thomas Lübbers1, Alexander Flohr, Synese Jolidon

  • 1Discovery Chemistry, F. Hoffmann-La Roche Ltd, Grenzacher Strasse 124, 4070 Basel, Switzerland. thomas.luebbers@roche.com

Bioorganic & Medicinal Chemistry Letters
|September 20, 2011
PubMed
Summary

Researchers discovered new aminothiazole compounds that reduce toxic amyloid beta (Aβ) peptide production without inhibiting γ-secretase. These novel modulators show promise in Alzheimer's disease research by decreasing harmful Aβ42 levels in vivo.

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Modeling Amyloid-&#946;42 Toxicity and Neurodegeneration in Adult Zebrafish Brain
10:01

Modeling Amyloid-β42 Toxicity and Neurodegeneration in Adult Zebrafish Brain

Published on: October 25, 2017

Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Drug Discovery

Background:

  • Amyloid beta (Aβ) peptides, particularly Aβ42, are implicated in Alzheimer's disease pathogenesis.
  • γ-secretase plays a crucial role in amyloid precursor protein processing and Aβ production.

Purpose of the Study:

  • To discover and characterize novel γ-secretase modulators (GSMs) with an aminothiazole core.
  • To investigate the effect of these compounds on Aβ peptide production, focusing on reducing toxic Aβ42.

Main Methods:

  • High-throughput screening (HTS) to identify initial hits.
  • Chemical synthesis of novel aminothiazole derivatives.
  • In vitro assays to measure Aβ peptide production.
  • Structure-Activity Relationship (SAR) studies.
  • In vivo studies in APPSwe transgenic mice.

Main Results:

  • Discovery of a new class of γ-secretase modulators featuring an aminothiazole scaffold.
  • Compounds exhibited moderate to good in vitro potency in reducing overall Aβ production.
  • These modulators selectively shifted Aβ production from aggregating Aβ42 to smaller, non-aggregating forms, without inhibiting γ-secretase activity.
  • Compound 15 demonstrated efficacy in reducing brain Aβ42 levels in vivo in a mouse model of Alzheimer's disease.

Conclusions:

  • The novel aminothiazole-based compounds represent a promising new class of γ-secretase modulators.
  • These compounds offer a potential therapeutic strategy for Alzheimer's disease by reducing toxic Aβ42 species.
  • Further development of these GSMs could lead to effective treatments for Alzheimer's disease.