ABSTRACT
ATP-sensitive potassium [K[ATP]] channel openers have a relaxation effect due to the lower cellular membrane potential and inhibit calcium influx. There has been considerable interest in exploring K[ATP] channel openers in the treatment of various diseases such as cardiovascular, cerebrovascular, and urinary system disease and premature labor. The purpose of this study was to synthesize 3,3,6,6-tetramethy l-9-aryl-octahydro-1,8-acridindiones and investigate their effects on vascular potassium channels and mechanism of induced relaxations on phenylephrine-induced contractile responses in isolated rings of rat aortic smooth muscle. In this study, four new derivatives of 3,3,6,6-tetramethy l-9-aryl-octahydro-1,8-acridindione [2a-d] were synthesized by the reaction of 5, 5-dimethyl-1,3-cyclohexanedione with an aromatic aldehyde, 2-alkylthio-1-[4-fluorobenzyl]-5-formylimidazole or 3-substituted benzaldehyde, in the presence of ammonia in methanol. Their effects on vascular potassium channels and mechanism of induced relaxations on phenylephrine-induced contractile responses in isolated rat aorta were investigated. Minoxidil was used as a standard potassium channel opener and Glibenclamide was used as a standard potassium channel blocker. The effects of compounds on KCl-induced contractile response which is an indicator of ca-channel blocking activity was also investigated and compared to that of nifedipine as a standard calcium channel blocker. Compounds 3a-d and Minoxidil relaxed the contractions exerted by using phenylephrine with the potency order as follows: Minoxidil > 3c > 3d > 3a > 3b. This effect was sensitive to the potassium channel blocker Glibenclamide. It can be concluded that these compounds act via ATP-sensitive potassium [K[ATP]] channels. Selectivity index [SI] for these compounds and Minoxidil also shows that these compounds are selective to ATP-sensitive potassium [K[ATP]] channels and the selectivity of compounds 3a-d is less than Minoxidil.
ABSTRACT
Calcium-channel Mockers have an important role in the treatment of several cardiovascular disorders. Derivatives of 1, 4-dihydropyridine are one of the most potent calcium antagonists. In this study four novel 1, 4-dihydropyridine calcium channel blockers were synthesized and their hypotensive properties were investigated in male rats. Four 1, 4-dihydropyridines bearing l-[4-fluorobenzyl]-54midazoIyl substituent at 4 position [5a-d] were synthesized and tested for hypotensive activity in male rats. The animal was anaesthetized and the right jugular vein was cannulated for the administration of test agents. The left carotid artery was cannulated and connected to a pressure transducer for continuous monitoring of arterial blood pressure. All synthesized compounds lowered rat blood pressure significantly in comparison with DMSO as vehicle and nifedipine as positive control. The hypotensive effects of all compounds were less than that of nifedipine at 2 and 4 mg/kg [P< 0.05]. The order of their effects on mean arterial blood pressure [MABP] was 5b>5c>5a>5d at dose of 4 mg/kg [P< 0.05]. All compounds tested increased heart rate in comparison with DMSO [P< 0.05]. The chronotropic effect of nifedipine was significantly less than synthesized compounds at dose of 4 mg/kg [P< 0.01]. The results showed that these novels 1, 4-dihydropyridines decreased mean arterial blood pressure [MABP] significantly, while increased heart rate in rat
ABSTRACT
Seven analogues of nifedipine [in which the ortho nitrophenyl group at position 4] were replaced by 2-alkylthio-1-[halobenzyl-5-imidazolyl substituent] were synthesized and evaluated as calcium antagonists using the high K[+] contraction of rat ileal longitudinal smooth muscle. These analogues of nifedipine decreased the various contractile responses of the longitudinal smooth muscle of the isolated rat ileum in a dose-dependent manner. However, their potencies for inhibition of contraction varied significantly from each other. All tested compounds [except compound 5f], were stronger than nifedipine with IC50 1.16 x 10[-13]M. Compound 5a with IC[50] 6.73 x 10[-15]M was the most active compound tested