Synthesis And Bioactivities Of3,16-bisammoniosteroidal Neuromuscular Blocking Agents

This paper are composed of5chapters themed by the synthesis and bioactivity of3,16-bisammoniosteroidal NMBAs.In chapter1, Physiology and pharmacology of muscle relaxants were brieffed, as well as the history of NMBAs. Then, NMBAs were classified by mechanism and structure. Some representatives of each category were detailed in terms of pharmacodynamics and pharmacokinetics. Next, the cause of the side effects of NMBAs were depicted.In chapter2, the basis of this study were illustrated. First, the common SAR of NMBAs, especially the steroidal type, were introduced in detail. Then, the research progress on ligand-recceptor interaction at atomic level were briefly reviewed. At last, the design scheme of this work was presented.In chapter3, the synthesis of bisammoniosteroidal NMBAs were introduced. Using epiandrosterone as raw material,105new compounds were obtained during7steps to the target molecule with satisfactory yields. All compounds were structurally confirmed by1H NMR,13C HMR, MS and elemental analysis. Absolute configuration were determined by the X-ray crystallography of the N-methypiperazino derivates (7c and12c).In chapter4, the neuromuscular blocking activity of target compounds were tested on the preparations of mouse phrenic nerve-hemidiaphragm, among which five compounds exhibiting good activity. The ED50values of compounds25’a-c are close to roccuronium and that of26’c and27’c are between vecuronium and rocuronium. Besides, the SAR of this series were reduced from the bioassay data.In chapter5, adult mouse nAChR were homology-modeled and were subsequently docked with one of the target molecule to probe the interaction between steroidal NMBAs and the binding pockect.