ABSTRACT
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.
ABSTRACT
<p><b>AIM</b>To observe the effect of LPC on the pacemaker current I(f) in ischemic myocardium and if the effect could be reversed by ISO.</p><p><b>METHODS</b>By using two microelectrode voltage clamp technique to measure and compare the amplitude of I(f) of ischemic myocardium in the presence of LPC and LPC add ISO.</p><p><b>RESULTS</b>Ischemia decreased the amplitude of I(f) at all membrane potential levels. Adding LPC 2 x 10(-5) mol/L to the ischemia-like solution, the amplitude of I(f) decreased further (n = 5, P < 0.05), it means that LPC aggravated the inhibitory effect of "ischemia" on the pacemaker activity. Adding LPC 2 x 10(-5) mol/L and ISO 1 x 10(-6) mol/L together to the ischemia-like solution, the amplitude of I(f) increased significantly at membrane potential -90 mV to - 120 mV (n = 8, P < 0.05) compared with ischemia condition, but still did not reach the levels before ischemia.</p><p><b>CONCLUSION</b>In acute myocardial ischemia condition, toxic metabolite LPC accentuated its inhibitory effect on pacemaker current I(f), a local release and accumulation of catecholamine could not completely reverse their inhibitory effect.</p>