Gramine derivatives targeting Ca2+ channels and Ser/Thr phosphatases: A new dual strategy for the treatment of neurodegenerative diseases

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.6b00478We 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 diseasesThis 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 Madri

Altered mitochondrial function, calcium signaling, and catecholamine release in chromaffin cells of diabetic and SHR rats

Comorbidity of diabetes and hypertension is frequent. Here, we have performed a comparative study in three animal models namely, normotensive Wistar Kyoto (WKY) rats, streptozotocin-induced diabetic rats (STZ), and spontaneously hypertensive rats (SHR). With respect WKY rats, we have found the following alterations in adrenal chromaffin cells from STZ and SHR rats: (1) diminished Ca2+ currents; (2) augmented [Ca2+](c) elevations and catecholamine release in cells stimulated with angiotensin II or high K+; (3) unchanged expression of angiotensin II receptors AT(1) and AT(2); (4) higher density of secretory vesicles at subplasmalemmal sites; (5) mitochondria with lower cristae density that were partially depolarized; and (6) lower whole cell ATP content. These alterations may have their origin in (i) an augmented capacity of the endoplasmic reticulum Ca2+ store likely due to (ii) impaired mitochondrial Ca2+ uptake; (iii) augmented high-[Ca2+](c) microdomains at subplasmalemmal sites secondary to augmented calcium-induce calcium release and to inositol tris-phosphate receptor mediated enhanced Ca2+ mobilization from the endoplasmic reticulum; and (iv) augmented vesicle pool. These alterations seem to be common to the two models of human hypertension here explored, STZ diabetic rats and SHR hypertensive rats.Ministerio de Economia y Competitividad, SpainCABICYCUAM/Bioiberica, SpainFundacion Teofilo Hernando, Madrid, SpainCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Univ Autonoma Madrid, Fac Med, Inst Teofilo Hernando, Madrid 28029, SpainUniv Autonoma Madrid, Fac Med, Dept Farmacol & Terapeut, Madrid 28029, SpainUAM, Hosp Univ Princesa, Inst Invest Sanitaria, Madrid, SpainUniv Fed Sao Paulo, UNIFESP, Dept Pharmacol, Sao Paulo, SP, BrazilUniv Castilla La Mancha, Fac Med, Dept Ciencias Med, Ciudad Real 13005, SpainUniv Fed Sao Paulo, UNIFESP, Dept Pharmacol, Sao Paulo, SP, BrazilMinisterio de Economia y Competitividad, Spain: SAF 2013-44108Ministerio de Economia y Competitividad, Spain: FPI BES-2014-069005CAPES: BEX 8477/13-2Web of Scienc