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 (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.
State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, 185# Donghu Rd, Wuhan 430071, China.
Hao
H
Hu
Zhigang
Z
Rao
Jianrong
J
Xu
Qingfu
Q
Zhu
Hans-Josef
HJ
Altenbach
Hongzhuan
H
Chen
Dingshan
D
Zhou
Yuling
Y
Xiao
Xianbing
X
Ke
Hao
H
Guo
Zhongyuan
Z
Wu
Peng
P
Liu
Xianming
X
Hu
D000818:Animals; D003964:Diaphragm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D008024:Ligands; D015335:Molecular Probes; D009025:Morpholines; D009466:Neuromuscular Blocking Agents; D000644:Quaternary Ammonium Compounds; D011978:Receptors, Nicotinic; D013256:Steroids