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Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis
Department of Biochemistry & Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
The Research Institute of the McGill University Health Centre, Montreal, Quebec, H3G 1A4, Canada
Department of Medicine, McGill University, Montreal, Quebec, H3G 1A4, Canada
Samaritan Pharmaceuticals, Las Vegas, NV 89109, USA
Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, H3G 1A4, Canada
* Author to whom correspondence should be addressed.
Received: 27 July 2009; in revised form: 14 August 2009 / Accepted: 1 September 2009 / Published: 3 September 2009
Abstract: Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimer’s disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-1-(tert-butyl-1H-indol-3-yl-methyl)-2-oxo-ethyl]-4-nitrobenzamide (SP-10) inhibits dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI) expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a compensatory mechanism aimed at maintaining cholesterol levels. SP-10 also induced a redistribution of filamentous (F-) and monomeric (G-) actin, leading to decreased actin levels in the submembrane cytoskeleton suggesting that SP-10-induced changes in actin distribution might prevent the formation of microvilli–cellular structures required for SRBI-mediated cholesterol uptake in adrenal cells.
Keywords: steroid synthesis; cholesterol uptake; cortisol; adrenal; neuroprotection
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MDPI and ACS Style
Xu, J.; Lecanu, L.; Tan, M.; Greeson, J.; Papadopoulos, V. Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis. Molecules 2009, 14, 3392-3410.
Xu J, Lecanu L, Tan M, Greeson J, Papadopoulos V. Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis. Molecules. 2009; 14(9):3392-3410.
Xu, Jing; Lecanu, Laurent; Tan, Matthew; Greeson, Janet; Papadopoulos, Vassilios. 2009. "Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis." Molecules 14, no. 9: 3392-3410.