6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade.

Several 4H-pyran derivatives were designed and synthesized previously as vasorelaxant agents for potential antihypertensive drugs. In this context, the objective of the present investigation was to determine the functional mechanism of vasorelaxant action of 6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1: ) and its in vivo antihypertensive effect. Thus, compound 1: showed significant vasorelaxant action on isolated aorta rat rings pre-contracted with serotonin or noradrenaline, and the effect was not endothelium-dependent. Compound 1: induced a significant relaxant effect when aortic rings were contracted with KCl (80 mM), indicating that the main mechanism of action is related to L-type calcium channel blockade. Last was corroborated since compound 1: induced a significant concentration-dependent lowering of contraction provoked by cumulative CaCl2 adding. Moreover, compound 1: was capable to block the contraction induced by FPL 64176, a specific L-type calcium channel agonist, in a concentration-dependent manner. On the other hand, docking studies revealed that compound 1: interacts on two possible sites of the L-type calcium channel and it had better affinity energy (-7.80+/-0.00 kcal/mol on the best poses) than nifedipine (-6.86+/-0.14 kcal/mol). Finally, compound 1: (50 mg/kg) showed significant antihypertensive activity, lowering the systolic and diastolic blood pressure on spontaneously hypertensive rats (SHR) without modifying heart rate.

Antihypertensive and vasorelaxant mode of action of the ethanol-soluble extract from Tagetes lucida Cav. aerial parts and its main bioactive metabolites.

ETHNOPHARMACOLOGICAL RELEVANCE: Tagetes lucida Cav. commonly known as "yauhtli" or "pericón" is used in Mexican traditional medicine for the treatment of anxiety, depressant diseases, pain, hypertension, among others. AIM: To evaluate the antihypertensive and vasorelaxant modes of action of a crude ethanolic extract from T. lucida aerial parts and to isolate the bioactive compounds. MATERIALS AND METHODS: Ethanolic extract was tested in an in vivo assay in SHR rats by intragastric administration at 10 and 100 mg/kg dosages, to measure and to compare hemodynamic parameters like diastolic and systolic blood pressure and heart rate. Also, extract (3.03-1000 µg/ml), fractions (3.03-1000 µg/ml) and pure isolated compounds (1.75-550 µM) were evaluated on isolated aortic rings contracted with noradrenaline (0.1 µM) to determine their vasorelaxant effect and extract-mode of action. RESULTS: Ethanolic extract of T. lucida lowered systolic and diastolic blood pressure on SHR rats without heart rate modification (P > 0.05). Moreover, the extract showed concentration-dependent relaxant effect in a partially endothelium-dependent manner (P < 0.05), through NO/cGMP system activation and calcium channel blockade. 6,7,8-trimethoxycoumarin (1), 6,7-dimethoxycoumarin (2), and 7-methoxycoumarin (3) from T. lucida are the main bioactive compounds of the extract and showed significant vasorelaxant activity. CONCLUSIONS: Results provide evidence and endorsed the antihypertensive properties attributed to T. lucida in traditional medicine, which is produced by vasorelaxant effect mainly through multitarget NO/cGMP system activation and calcium channel blockade. Coumarin derivatives 1, 2 and 3 are the responsible of the vasorelaxant activity.

Synthesis, ex vivo and in silico studies of 3-cyano-2-pyridone derivatives with vasorelaxant activity.

An efficient and simple synthesis of 3-cyano-2-pyridone derivatives (6a-f) through 3,4-dihydropyridin-2-one oxidation process is described. A greener method to synthesize 3,4-dihydropyridin-2-one has also been developed by rearranging 4H-pyran (4a-f) derivatives in aqueous medium applying H2SO4 as the catalyst source and microwave irradiation. The vasorelaxant activity of 3-cyano-2-pyridone derivatives (6a-f) was proved on isolated thoracic aorta rat rings with and without endothelium (+E and -E, respectively) pre-contracted with noradrenaline (0.1 µM). All compounds exhibited significant concentration-dependent and endothelium-independent vasorelaxant effects being the nitro derivatives (6a and f) and compound 6d the most potent with EC50 of 7, 4.4 and 5 µM, respectively. Finally, a previously described 3D model of the central pore of human L-type calcium channel (LCC), modified to be on agreement with NCBI sequence NP_005174.2 for subunit alpha-1F isoform 1, was used to dock most active compounds. 6a, d and f lowest affinity energy structures were found docked in the same cavity conformed by IS6, IS5, IP and IIS6 helices. Nifedipine lowest energy structure was found in the cavity formed by IIS6, IIS5, IIP and IIIS6. Although nifedipine docked in a different cavity, the superposition of both, allowed us to observe that they were almost the same cavities, indicating that there exist subtle steric differences that lead to a different docking for nifedipine. All compounds docked with similar free energy of binding.

Ex vivo study of the vasorelaxant activity induced by phenanthrene derivatives isolated from Maxillaria densa.

The phenanthrenes gymnopusin (1), fimbriol A (2), and erianthridin (3) from Maxillaria densa were found to induce significant relaxant effects in a concentration-dependent and endothelium-independent manner on aortic rings precontracted with norepinephrine (NE, 0.1 µM) and KCl (80 mM). Compound 1 was the most active and also inhibited the cumulative concentration-response contraction of NE or CaCl(2). Contractions induced by FPL 64176, an agonist of L-type voltage-dependent calcium channels, were blocked by 1. The potassium channel blockers glibenclamide and TEA (tetraethylammonium) reduced the relaxations induced by 1. Nevertheless, the effect of 1 was not modified by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific soluble guanylate cyclase inhibitor. The functional results obtained suggest that 1 induces relaxation through an endothelium-independent pathway by the control of cationic channels (calcium channel blockade and potassium channel opening) in the myogenic response of rat aortic rings.