The Antagonistic Activity And Qsar Of Tropane Compounds To Muscarinic M3 Receptors And Their Inhibition To Neutrophil Elastase

Objective:Chronic obstructive pulmonary disease?COPD?is a serious disease that endangers respiratory health.At present the M3 receptor antagonists are preferred for COPD to relieve the symptoms through bronchiectasis in clinics.In this paper,based on the previous work,a series of new compounds were designed and synthesized by modifying the C-3?position on the tropane skeleton,and then the antagonistic activity to muscarinic M3 receptors was evaluated.The clues of structural optimization were obtained by quantitatively analyzing their structure-activity relationship to guide subsequent molecular design.Generally,COPD is associated with abnormal pulmonary inflammation.The clinical practice shows that M3 receptor antagonists also have anti-inflammatory effect.As Neutrophil Elastase?NE?is a key factor in pulmonary inflammatory reaction,therefore,further studies for the newly synthesized compounds were carried out on the inhibition to NE.The results were afforded as the theoretical reference to the develop of medicines with high both NE inhibition and M3 receptor antagonistic activities.Methods:1.A series of new 3?-acyloxytropanes were designed by taking the structures of M3 receptor antagonist tiotropium bromide and NE-specific inhibitor sivelestat sodium as the reference.3?-hydroxy-tropane?J0?was used as the starting material to synthesized these new compounds through acylation reaction.2.The isolated bronchus with rich M3 receptors on guinea pigs was selected as the sample for testing the antagonistic parameter pA₂ of new compounds to M3 receptors,and the qualitative structure-activity relationship was preliminarily analyzed.3.The antagonistic parameter pA₂ to M3 receptors of targets and some tropane compounds synthesized in former studies was applied to build quantitative structure-activity relationship?QSAR?.The effects of steric field and electrostatic field on M3antagonistic activity were analyzed.The toxicity of compounds for QSAR model was predicted by several professional softwares to estimate their security.4.The hydrolysis of the substrate PGlu-Pro-Val-PNA could be specifically catalyzed by NE to produce colored 4-Nitroaniline?PNA?.The inhibition rate of targets to NE was acquired by measuring the absorbance of the reaction mixture.The qualitative structure-activity relationship of targets to NE inhibitory activity was preliminarily analyzed.Results:6 new tropane compounds were prepared.All targets showed obvious antagonistic activity to M3 receptors.Among them,J4 had the greatest activity?pA₂=7.992?.The cross-validation correlation coefficient squared?q²?,non-cross-validated correlation coefficient squared?r²?of QSAR model were 0.585,0.993 respectively and the model was confirmed to be valid.J2,J5 and J6 had obvious NE activity with inhibition rates of 19.30%,20.18%and 23.81%respectively.Conclusion:In this study,we firstly found that when the acetoxyl was introduced in the R-substituting group of C-3?position on the tropane skeleton,the antagonistic activity of compounds to muscarinic M3 receptors could be obviously improved.The results suggested that there may be multiple hydrogen bond donors or receptors in the relevant domain of M3 receptors.If the?-conjugated rings in the R group were enlarged and O or N atoms participate in p-?conjugation,the M3 antagonistic activity could be largely increased.The phenyl in the R group of C-3?position may be essential for NE inhibition activity.The introduction of strong electron-withdrawing atom or group on the phenyl ring was beneficial for improving NE inhibitory activity.The less correlation exists between NE inhibition and M3 antagonistic activities of tropane compounds.The benzoyloxytropanes with CF₃ group on the phenyl ring of C-3?position had certain dual activities.