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Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration.
ACS Chem Neurosci. 2015 Sep 16; 6(9):1626-36.AC

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+Show Affiliations

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.Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.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.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.Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , C/Arzobispo Morcillo, 4, 28029 Madrid, Spain.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26192029

Citation

Martínez-Sanz, Francisco J., et al. "Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration." ACS Chemical Neuroscience, vol. 6, no. 9, 2015, pp. 1626-36.
Martínez-Sanz FJ, Lajarín-Cuesta R, Moreno-Ortega AJ, et al. Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration. ACS Chem Neurosci. 2015;6(9):1626-36.
Martínez-Sanz, F. J., Lajarín-Cuesta, R., Moreno-Ortega, A. J., González-Lafuente, L., Fernández-Morales, J. C., López-Arribas, R., Cano-Abad, M. F., & de los Ríos, C. (2015). Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration. ACS Chemical Neuroscience, 6(9), 1626-36. https://doi.org/10.1021/acschemneuro.5b00161
Martínez-Sanz FJ, et al. Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration. ACS Chem Neurosci. 2015 Sep 16;6(9):1626-36. PubMed PMID: 26192029.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration. AU - Martínez-Sanz,Francisco J, AU - Lajarín-Cuesta,Rocío, AU - Moreno-Ortega,Ana J, AU - González-Lafuente,Laura, AU - Fernández-Morales,Jose C, AU - López-Arribas,Raquel, AU - Cano-Abad,María F, AU - de los Ríos,Cristóbal, Y1 - 2015/07/31/ PY - 2015/7/21/entrez PY - 2015/7/21/pubmed PY - 2016/6/15/medline KW - Benzothiazepines KW - NCLX KW - mNCX KW - mitochondria KW - neurodegeneration KW - neuroprotection SP - 1626 EP - 36 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 6 IS - 9 N2 - 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. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/26192029/Benzothiazepine_CGP37157_Analogues_Exert_Cytoprotection_in_Various_in_Vitro_Models_of_Neurodegeneration_ L2 - https://doi.org/10.1021/acschemneuro.5b00161 DB - PRIME DP - Unbound Medicine ER -