16-Morpholino quaternary ammonium steroidal derivatives as neuromuscular blocking agents: Synthesis, biological evaluation and in silico probe of ligand–receptor interaction

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 (IC50 = 3.49 μM) and 3β-N-methylbenzylamino derivate 8g (IC50 = 4.54 μM), showing activity close to rocuronium (IC50 = 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.

The most potent compound in the tested series, 3-piperridine derivate, was shown. The two possible binding modes were revealed by docking it to the modeled pocket (pink – lipophilic area; green – hydrophilic area).Figure optionsDownload as PowerPoint slideHighlights
► The configurations of 3α/β were confirmed by 1H NMR and X-ray crystallography.
► There were two compounds showing activity close to rocuronium.
► The preliminary SAR was concluded with the calculated N–N distance and log P.
► Ligand–receptor interactions were revealed with the homology-modeled mouse nAChR.