2 research outputs found
Carbazole ligands as c-myc G-quadruplex binders
The interactions of c-myc G-quadruplex with three carbazole derivatives were investigated by UV-Vis spectrophotometry, fluorescence, CD spectroscopy, and molecular modeling. The results showed that a combination of carbazole scaffold functionalized with ethyl, triazole and imidazole groups resulted in stabilization of the intramolecular G-quadruplex formed by the DNA sequence derived from the NHE III1 region of c-myc oncogene (Pu22). Binding to the G-quadruplex Pu22 resulted in the significant increase in fluorescence intensity of complexed ligands 1-3. All ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G-quadruplex with comparable affinity, which agrees with binding model of end-stacking on terminal G-tetrads
Selective Modulation of Ī±5 GABAA Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimerās Disease
Selective negative allosteric modulators (NAMs), targeting Ī±5 subunit-containing GABAA receptors (GABAARs) as potential therapeutic targets for disorders associated with cognitive deficits, including Alzheimerās disease (AD), continually fail clinical trials. We investigated whether this was due to the change in the expression of Ī±5 GABAARs, consequently altering synaptic function during AD pathogenesis. Using medicinal chemistry and computational modeling, we developed aqueous soluble hybrids of 6,6-dimethyl-3-(2-hydroxyethyl) thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophene-4(5H)-one, that demonstrated selective binding and high negative allosteric modulation, specifically for the Ī±5 GABAAR subtypes in constructed HEK293 stable cell-lines. Using a knock-in mouse model of AD (APPNLāF/NLāF), which expresses a mutant form of human amyloid-Ī² (AĪ²), we performed immunofluorescence studies combined with electrophysiological whole-cell recordings to investigate the effects of our key molecule, Ī±5-SOP002 in the hippocampal CA1 region. In aged APPNLāF/NLāF mice, selective preservation of Ī±5 GABAARs was observed in, calretinin- (CR), cholecystokinin- (CCK), somatostatin- (SST) expressing interneurons, and pyramidal cells. Previously, we reported that CR dis-inhibitory interneurons, specialized in regulating other interneurons displayed abnormally high levels of synaptic inhibition in the APPNLāF/NLāF mouse model, here we show that this excessive inhibition was ānormalizedā to control values with bath-applied Ī±5-SOP002 (1 Ī¼M). However, Ī±5-SOP002, further impaired inhibition onto CCK and pyramidal cells that were already largely compromised by exhibiting a deficit of inhibition in the AD model. In summary, using a multi-disciplinary approach, we show that exposure to Ī±5 GABAAR NAMs may further compromise aberrant synapses in AD. We, therefore, suggest that the Ī±5 GABAAR is not a suitable therapeutic target for the treatment of AD or other cognitive deficits due to the widespread neuronal-networks that use Ī±5 GABAARs