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

• Published in: Journal of medicinal chemistry Vol. 59; no. 13; p. 6265
• Main Authors: Lajarín-Cuesta, Rocío, Nanclares, Carmen, Arranz-Tagarro, Juan-Alberto, González-Lafuente, Laura, Arribas, Raquel L, Araujo de Brito, Monique, Gandía, Luis, de Los Ríos, Cristóbal
• Format: Journal Article
• Language: English
• Published: United States 14.07.2016
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Animals; Calcium Channels - metabolism; Cattle; Cell Survival - drug effects; Dose-Response Relationship, Drug; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Molecular Structure; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00478

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.