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Gramine Derivatives Targeting Ca(2+) Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases.

Abstract：

: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 Ca(2+) 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 Ca(2+) through VGCC, as measured by Fluo-4/AM and patch clamp techniques, and protected in Ca(2+) 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lajarín-Cuesta R,Nanclares C,Arranz-Tagarro JA,González-Lafuente L,Arribas RL,Araujo de Brito M,Gandía L,de Los Ríos C

doi

10.1021/acs.jmedchem.6b00478

subject

Has Abstract

pub_date

2016-07-14 00:00:00

pages

6265-80

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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