Gramine Derivatives Targeting Ca(2+) Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases.
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.
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
Rocío
R
Lajarín-Cuesta
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
Carmen
C
Nanclares
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
Juan-Alberto
JA
Arranz-Tagarro
Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa , C/Diego de León, 62, 28006 Madrid, Spain.
Laura
L
González-Lafuente
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
Raquel L
RL
Arribas
Programa de Pós Graduação em Ciências Aplicadas a Produtos Para a Saúde, Faculdade de Farmácia, Universidade Federal Fluminense , Niterói, Rio de Janeiro, Brasil.
Monique
M
Araujo de Brito
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
Luis
L
Gandía
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.|Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa , C/Diego de León, 62, 28006 Madrid, Spain.
Cristóbal
C
de Los Ríos
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D015220:Calcium Channels; D026121:Indole Alkaloids; D010749:Phosphoprotein Phosphatases; C007884:gramine