Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-β and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications
| Autor: | Frank M. LaFerla, Haruhiko Fuwa, Luis M. Botana, Mercedes R. Vieytes, Makoto Sasaki, Lydia Giménez-Llort, Yuto Suga, Tomomi Goto, Yu Konno, Carmen Vale, Eva Alonso |
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| Rok vydání: | 2012 |
| Předmět: |
Tau pathology
Stereochemistry Cell Survival Transgene Ether Mice Transgenic tau Proteins 010402 general chemistry 01 natural sciences Biochemistry Receptors N-Methyl-D-Aspartate Catalysis Ciguatoxins chemistry.chemical_compound Mice Colloid and Surface Chemistry Alzheimer Disease Neurotoxin Animals Humans Receptor Cells Cultured Cerebral Cortex Neurons Amyloid beta-Peptides 010405 organic chemistry Chemistry Biological activity General Chemistry Voltage-gated potassium channel Potassium channel 0104 chemical sciences Potassium Channels Voltage-Gated |
| Zdroj: | Journal of the American Chemical Society |
| ISSN: | 1520-5126 |
| Popis: | Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K(v) channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (K(v)) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aβ) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K(+) currents, a reduction in the extra- and intracellular levels of Aβ, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K(v) channels as well as the molecular mechanism of Aβ metabolism modulated by NMDA receptors. |
| Databáze: | OpenAIRE |
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