Abstract
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, 3β-piperidino derivate 8d (IC(50) = 3.49 μM) and 3β-N-methylbenzylamino derivate 8g (IC(50) = 4.54 μM), showing activity close to rocuronium (IC(50) = 2.50 μM). 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 α7 nAChR as intermediary template.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Diaphragm / drug effects
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Dose-Response Relationship, Drug
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Ligands
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Male
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Mice
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Molecular Probes / chemical synthesis
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Molecular Probes / chemistry
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Molecular Probes / pharmacology*
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Molecular Structure
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Morpholines / chemical synthesis
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Morpholines / chemistry
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Morpholines / pharmacology*
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Muscle, Skeletal / drug effects
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Neuromuscular Blocking Agents / chemical synthesis
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Neuromuscular Blocking Agents / chemistry
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Neuromuscular Blocking Agents / pharmacology*
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Neurons / drug effects
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Quaternary Ammonium Compounds / chemical synthesis
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Quaternary Ammonium Compounds / chemistry
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Quaternary Ammonium Compounds / pharmacology*
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Receptors, Nicotinic / metabolism*
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Steroids / chemical synthesis
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Steroids / chemistry
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Steroids / pharmacology*
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Structure-Activity Relationship
Substances
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Ligands
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Molecular Probes
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Morpholines
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Neuromuscular Blocking Agents
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Quaternary Ammonium Compounds
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Receptors, Nicotinic
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Steroids