Gramine derivatives targeting Ca2+ channels and Ser/Thr phosphatases: A new dual strategy for the treatment of neurodegenerative diseases
Entity
UAM. Departamento de FarmacologíaPublisher
American Chemical SocietyDate
2016-06-09Citation
10.1021/acs.jmedchem.6b00478
Journal of Medicinal Chemistry 59.13 (2016): 6265–6280
ISSN
0022-2623 (print); 1520-4804 (online)DOI
10.1021/acs.jmedchem.6b00478Funded by
This work was supported by the following grant: Proyectos de Investigación en Salud (PI13/00789, IS Carlos III). R.L.C is granted by Universidad Autónoma de MadridEditor's Version
http://dx.doi.org/10.1021/acs.jmedchem.6b00478Subjects
Alzheimer’s disease; Neurodegenerative diseases.; Gramine; FarmaciaNote
This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry , copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00478Rights
© 2016 American Chemical SocietyAbstract
We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer’s disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca2+ channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatases, which have been marginally aimed, even despite their key role in protein τ dephosphorylation. Twenty-five compounds were synthesized, and mostly their neuroprotective profile exceeded that offered by the head compound gramine. In general, these compounds reduced the entry of Ca2+ through VGCC, as measured by Fluo-4/AM and patch clamp techniques, and protected in Ca2+ overload-induced models of neurotoxicity, like glutamate or veratridine exposures. Furthermore, we hypothesize that these compounds decrease τ hyperphosphorylation based on the maintenance of the Ser/Thr phosphatase activity and their neuroprotection against the damage caused by okadaic acid. Hence, we propose this multitarget approach as a new and promising strategy for the treatment of neurodegenerative diseases
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Google Scholar:Lajarín-Cuesta, Rocío
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Nanclares, Carmen
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Arranz-Tagarro, Juan Alberto
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González-Lafuente, Laura
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Arribas, Raquel A.
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Araujo de Brito, Monique
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Gandía Juan, Luis
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Ríos, Cristóbal de los
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