Background: Vasoconstriction is a major pathological feature of cardiovascular diseases
involving endothelium dependent and independent mechanisms. Oxadiazole moiety appeared to be effective
in various pathologies.
Objective: The aim of the study was to synthesize and evaluate the mechanism of vasorelaxation exhibited
by synthesized oxadiazole derivatives.
Method: The 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized by an efficient and simple method. The derivatives
were investigated for their ex-vivo vasorelaxant action on intact/denuded endothelium rat aortic rings precontracted
with norepinephrine/ phenylephrine/KCl.
Results: The contractions induced in the aortic rings by the addition of cumulative concentrations of norepinephrine,
phenylephrine, KCl and calcium were significantly antagonized by a derivative, OXD-Z2. In another experiment, verapamil
pretreatment inhibited phenylephrine and Ca2+-induced aortic contractions and OXD-Z2 did not alter verapamilinduced
inhibition. This indicated the role of L-type Ca2+-channels in the OXD-Z2-induced vasorelaxation via inhibition
of calcium influx. Further, atropine (muscarinic receptor antagonist), L-NAME (NO synthase inhibitor) and methylene
blue (non-selective cGMP inhibitor) inhibited OXD-Z2-induced relaxation in other sets of experiments. These results indicate
that OXD-Z2 also mediates vasorelaxation through NO release by muscarinic receptor activation. In addition, the
molecular docking studies showed that OXD-Z2 interacts with L-type Ca2+-channel, muscarinic (M2) receptor and eNOS.
Conclusion: Thus, it is deduced from the above findings that the vasorelaxant activity of OXD-Z2 involves muscarinic
receptor-mediated nitric oxide release in addition to direct inhibition of L-type Ca2+-channels.