title: Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration.
abstract: Mitochondria regulate cellular Ca(2+) oscillations, taking up Ca(2+) through its uniporter and releasing it through the mitochondrial sodium/calcium exchanger. The role of mitochondria in the regulation of Ca(2+) cycle has received much attention recently, as it is a central stage in neuronal survival and death processes. Over the last decades, the 4,1-benzothiazepine CGP37157 has been the only available blocker of the mitochondrial sodium/calcium exchanger, although it targets several other calcium transporters. We report the synthesis of 4,1-benzothiazepine derivatives with the goal of enhancing mitochondrial sodium/calcium exchanger blockade and selectivity, and the evaluation of their cytoprotective effect. The compound 4c presented an interesting neuroprotective profile in addition to an important blockade of the mitochondrial sodium/calcium exchanger. The use of this benzothiazepine could help to understand the physiological functions of the mitochondrial sodium/calcium exchanger. In addition, we hypothesize that a moderate blockade of the mitochondrial sodium/calcium exchanger would provide enhanced neuroprotection in neurons.
authors.affiliation: 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.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Martínez-Sanz
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Lajarín-Cuesta
authors.affiliation: 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.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Moreno-Ortega
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: González-Lafuente
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Fernández-Morales
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: López-Arribas
authors.affiliation: 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.
authors.forename: María F
authors.initials: MF
authors.lastname: Cano-Abad
authors.affiliation: 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.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019439:Chromaffin Cells / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000608217:7-chloro-5-(2'-isopropylphenyl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one; D018696:Neuroprotective Agents; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D012964:Sodium; D002118:Calcium
keywords: Benzothiazepines; NCLX; mNCX; mitochondria; neurodegeneration; neuroprotection