RESUMO
Objective • To provide theoretical guidance for the design of molecules with high activity by building the quantitative structure-activity relationship (QSAR) model for tropane compounds as muscarinic M3 receptor antagonists. Methods • Six compounds (J1-J6) were prepared with 3α-hydroxy-tropane (J0) as the starting material by modifying the structure in C-3α position of the tropane skeleton. The antagonistic activity of new tropane compounds to muscarinic M3 receptors on tracheal rings of guinea pigs was evaluated by functional assays in vitro. The antagonistic parameters (pA2) of new tropane compounds prepared in this paper and former studies were applied to construct the QSAR model. The information about structural optimization was acquired by analyzing the effect of steric field and electrostatic field of model on activity of tropane compounds. Results • The six new tropane compounds showed obvious antagonistic activity against M3 receptors. Among them, J4 had the greatest activity (pA2=7.992). The cross-validation correlation coefficient squared (q2) and the non-cross-validated correlation coefficient squared (r2) of the QSAR model were 0.585 and 0.993, respectively. Conclusion • The antagonistic activity to muscarinic M3 receptors can be obviously improved, when the conjugating extent of π-bonds is large and O or N atoms participate in conjugation on the rings in the R-substituting group at C-3α position of the compounds.
RESUMO
Objective · To provide theoretical guidance for the design of molecules with high activity by building the quantitative structure-activity relationship (QSAR) model for tropane compounds as muscarinic M3 receptor antagonists. Methods · Six compounds (J1-J6) were prepared with3α-hydroxy-tropane (J0) as the starting material by modifying the structure in C-3α position of the tropane skeleton. The antagonistic activity of new tropane compounds to muscarinic M3 receptors on tracheal rings of guinea pigs was evaluated by functional assays in vitro. The antagonistic parameters (pA2) of new tropane compounds prepared in this paper and former studies were applied to construct the QSAR model. The information about structural optimization was acquired by analyzing the effect of steric field and electrostatic field of model on activity of tropane compounds. Results · The six new tropane compounds showed obvious antagonistic activity against M3 receptors. Among them, J4 had the greatest activity (pA2=7.992). The cross-validation correlation coefficient squared (q2) and the non-cross-validated correlation coefficient squared (r2) of the QSAR model were 0.585 and 0.993, respectively.Conclusion · The antagonistic activity to muscarinic M3 receptors can be obviously improved, when the conjugating extent of π-bonds is large and O or N atoms participate in conjugation on the rings in the R-substituting group at C-3α position of the compounds.
RESUMO
Objective · To design and synthesize five new tropane compounds, and test their antagonistic activity against M3 receptor and inhibition activity to neutrophil elastase (NE), of which the structure-activity relationship were preliminarily investigated. Methods · The five compounds, A1-A3,B1 and C1, were prepared with 3α-hydroxy-tropane (A0) as the starting material by modifying the structure in C-3α position and N atom on the tropane skeleton. The antagonistic activity of the compounds to muscarinic M3 receptors on tracheal rings of guinea pigs was evaluated by functional assays in vitro. The hydrolysis of PGlu-Pro-Val-PNA as substrate was catalyzed by NE to get colorful nitroaniline (PNA). The NE inhibition activity of the tropane compounds was obtained by determining the absorbance [(D(405 nm)] of PNA. Results · The five new tropane compounds generated strong antagonistic activity against M3 receptors. Among them, A2 had the greatest activity [antagonistic parameter pA2(M3)=9.004], and elicited obvious inhibitory effect to NE (inhibition ratio YA2=20.29%). Conclusion · Introducing strong electron-attraction group, such as sulfuryl and hydrophobic group with large volume into C-3α position on the tropane skeleton can improve the M3 receptor antagonistic activity as well as the NE inhibition activity.