Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue -, Pages 332-347Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.07.048
Keywords
Steroid; Neuromuscular blocking agent; Muscle relaxant; nAChR; Non-depolarizing agent
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Funding
- National Mega Project on Major Drug Development [2011ZX09401-302]
- National Natural Science Foundation of China [21102107]
- Fundamental Research Funds for the Central Universities
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A series of steroidal 3,16-bis-quaternary ammonium salts were synthesized and screened on mouse hemi-diaphragm to explore new steroidal neuromuscular blocking agents. There were two compounds, 3 beta-piperidino derivate 8d (IC50 = 3.49 mu M) and 3 beta-N-methylbenzylamino derivate 8g (IC50 = 4.54 mu M), showing activity close to rocuronium (IC50 = 2.50 mu M). The preliminary structure-activity relationship was deduced from the bioactivity results with the aid of the calculated N-N distance and log P. Meanwhile, the interactions between the ligand and binding pocket were revealed by docking 8d to the ligand binding domain of the mouse muscle nicotinic acetylcholine receptor (nAChR). This nAChR was modeled using Molecular Operating Environment (MOE) package indirectly from mollusca acetylcholine binding protein with mouse neuron alpha 7 nAChR as intermediary template. (C) 2012 Elsevier Masson SAS. All rights reserved.
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