Synthesis and Biological Activity of the Pyridine-hexacyclic-steroid Derivative on a Heart Failure Model

Abstract

Background: Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. Objective: The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. Methods: The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. Results: The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. Conclusion: It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.

Evaluation of biological activity of some pyridine derivatives on perfusion pressure and their interaction with the M2 muscarinic receptor

“…These data suggest that pyridine derivatives (6, 9 and 13) could interact with some biological molecules to produce changes in the cardiovascular system translated as changes in the perfusion pressure. Analyzing the hypothesis above mentioned and other reports which indicate that some pyridine derivatives produce changes in the perfusion pressure [13,14] through M2 muscarinic receptor activation. [15,16,[41][42][43] For this reason, in this research a theoretical evaluation on interaction of compounds 6, 9 and 13 with M2 muscarinic receptor was determinate.…”

“…It is important to mention that the dose used in this research was based on previously reported studies which indicate that some compounds can produce effects on cardiovascular system at a dose of 001 nM. [13,27]…”

“…[12] Furthermore, a study shows that Pyridine-hexacyclicsteroid derivative produce changes in the perfusion pressure using a heart failure model. [13] In addition, a report suggests that pyridinylsulfonylcarbamate derivative may cause changes in perfusion pressure in an isolated dog mesenteric strip. Other data show that 2-pyridine-aldoxime methyl chloride (pralidoxime) increase coronary perfusion pressure in a pig cardiopulmonary resuscitation model; [15] in addition, a study showed that pralidoxime increases mean arterial pressure and might have low affinity for M2 receptor in the heart.…”

Evaluation of Biological Activity Exerted by Dibenzo[b,e]Thiophene-11(6H)-One on Left Ventricular Pressure Using an Isolated Rat Heart Model

“…Analyzing these data and other reports which suggests that some dibenzo derivatives can exert changes in intracellular calcium levels 45 46 . Besides, it is important to mention that in the literature there are some studies indicating that nifedipine can block the positive inotropic activity of some compounds 47 48 49 ; for this reason in this study the biological activity produced by Dibenzo[b,e]thiophene-11(6H)-one on left ventricular pressure was evaluated en the absence or presence of nifedipine drug ( type-L calcium antagonist) 50 . The results showed that Dibenzo[b,e]thiophene-11(6H)-one increases left ventricular pressure in a dose-dependent manner and this effect was inhibited in the presence of nifedipine.…”