ABSTRACT
Objective:To determine the depressant-like effects and the possible mechanism of action of tilianin isolated from active methanol extract ofAgastache mexicana(A. mexicana).Also, to establish the pharmacophoric requirements of tilianin, as a possible ligand of GABAA/BZD receptor, by the alignment of diazepam, CGS-9896 and diindole, using a previously described pharmacophoric model.Methods:Tilianin (30 to 300 mg/kg,ip.and 300 mg/kg, po.)and methanol crude extract (10 to 300 mg/kg,ip. and 300 mg/kgpo.)fromA. mexicana were evaluated for potential sedative and anxiolytic-like response drugs by using open-field, hole-board, cylinder of exploration, plus-maze and sodium pentobarbital-induced hypnosis mice methods.Results:Methanol extract and tilianin showed anxiolytic-like activity from a dosage of 30 mg/kg,ip.or 300 mg/kg,po.and were less potent than diazepam 0.1 mg/kg, a reference anxiolytic drug used. Moreover, depressant activity of both potentiates sodium pentobarbital (SP)-induced sleeping time. The anxiolytic-like effect of 30 mg/kgip.observed for the extract and tilianin, by using the plus-maze model, was partially prevented in the presence of flumazenil (a GABAA/BZD antagonist, 5 mg/kgip.)but not in the presence of WAY 100635 (a selective 5-HT1A receptor antagonist, 0.32 mg/kg,ip.).Pharmacophoric modeling alignments of three agonist of GABAA/BZD allow identify seven chemical features. Tilianin contains six of the seven features previously determined.Conclusions:Results indicate that tilianin is one of the bioactive metabolites in the anxiolytic-like activity ofA. mexicana, reinforcing its central nervous system uses, where GABAA/BZD, but not 5-HT1A, receptors are partially involved.
ABSTRACT
Current work was conducted in order to determine the underlying mode of relaxant action of 7-ethoxy-4-methyl- 2H-chromen-2-one (1), a coumarin obtained by semisynthesis from umbelliferone (2), with significant relaxant effect in a concentration-dependent manner on tracheal rat rings pre-contracted with carbachol (1 μM). In a previous study it was demonstrated that compound 1 and 2 showed significant relaxant effect, being 1 the most active compound (Emax= 100% and EC50= 83 μM) even more active than theophylline an unspecific phosphodiesterases (PDE’s) inhibitor used as positive control. Moreover, pretreatment with 1 significantly shifted to the right the carbachol-induced contraction. On the other hand, compound 1 (83 μM) produces significant (100%) relaxant effect on the contraction induced by KCl (80 mM) and the CaCl2-induced contraction was significantly reduced by the coumarin 1 as nifedipine does (a L-type calcium channel blocker), used as positive control. Indomethacin (10 μM, unspecific COX inhibitor) significantly reduced 1-relaxation. Meanwhile, in the presence of isoproterenol (a -adrenergic agonist), and K+ channel blockers glibenclamide (10 μM) and 2- AP (100 μM) the relaxant curve was not modified. Compound 1 was docked on an outer cavity located on the extracellular side of the human L-type calcium channel model (affinity energy -6.8 kcal/mol). However, compound 1 was also found on the same location as nifedipine with the same affinity energy (-6.3 kcal/mol) as previously described. Both conformations were stabilized by aliphatic interactions on both binding sites, primordially by a π-π interaction between FIVS6.7 and aromatic rings from compound 1. In conclusion, 7-ethoxy-4- methyl-2H-chromen-2-one (1) induces a significant relaxant action on rat trachea rings, through L-type calcium channel blockade and, as a second mechanism of action, by a possible intracellular cyclic AMP increasing.
ABSTRACT
The aim of the current study was to investigate the vasorelaxant effect of several extracts from Laelia speciosa and Laelia anceps, on an ex vivo method using aorta rat rings with and without endothelium pre-contracted with norepinephrine (0.1 μM), in order to establish them as a real source for the isolation of bioactive compounds with potential use as antihypertensive agent. All extracts caused concentration-dependent relaxation in -precontracted aortic rings with and without endothelium; the most active extracts were the hexanic and dichlorometanic extracts from roots of L. anceps and L. speciosa (HERLanc, DERLanc, HERLspec and DERLspec, respectively), and were less potent than positive controls used (carbachol and sodium nitroprusside). These results suggest that secondary metabolites, responsible for the vasorelaxant activity, belong to a group of compounds of medium and low polarity, and the roots were the main tissues of the plant where the vasorelaxant compounds are stored. In conclusion, both orchids represent an ideal source for obtaining lead compounds for designing new therapeutic agents, with potential vasorelaxant and antihypertensive effects.