Effects of different coumarin- 3-carboxamide agents on scopolamine induced learning and memory deficit in mice

Introduction: It has been shown that three new synthetic coumarins-3-carboxamides including 3-fluorobenzilchloride, 4-fluorobenzilchloride and 2-hidroxy-3 metoxybenzaldehyde, have acetylcholinesterase inhibitory activity. This study was performed to estimate ameliorating effect of these new coumarin-3-carboxamides on memory impairments induced by scopolamine [1 mg/kg, induced prolongation] in mice

Methods: 30 male mice were divided into five groups, 6 mice in each group. Three experiment groups received coumarins-3- carboxamides [10 mg/kg body weight] 30 min before scopalamin injection and two other groups considered as normal [saline-treated] groups and finally one negative control [scopalamin only] group. The experiment groups were treated with coumarins of 3-fluorobenzilchloride, 4-fluorobenzilchloride and 2-hidroxy-3 metoxybenzaldehyde. The passive avoidance test was performed in an automatic conventional shuttle box set-up. The stepped down latency and number of errors was recorded

Results: With reference to saline-treated group, scopolamine-treated mice demonstrated impairment of learning and memory as a reduction of latency and an increased numbers of errors in step-down test]p < 0.01]. Treated mice receiving these coumarins at the dose of 10 mg/kg showed an increase in the number of avoidances on the memory tests compared to the scopolamine group [p < 0.01]

Conclusion: The study has demonstrated some therapeutic effects of coumarin-3-carboxamides on learning and memory deficit induced by scopolamine. Further investigation is needed to explore whether coumarin-3-carboxamides could be beneficial for memory impairment in Alzheimer's disease in which cholinergic deficit is one of the hallmarks

Synthesis and vasorelaxant effect of 9-aryl-1,8-acridinediones aspotassium channel openers in isolated rat aorta

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.

Synthesis of novel 4-[l-[4-fluorobenzyl]-5-imidazolyl] dihydropyridines and studying their effects on rat blood pressure

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

Synthesis and effects of 4,5-diaryl-2-[2-alkylthio-5-imidazolyl] imidazoles as selective cyclooxygenase inhibitors

In recent years highly selective COX-2inhibitors were withdrawn from the market because of an increased risk of cardiovascular complications. In this study we were looking for potent compounds with moderate selectivity for COX-2. So, four analogues of 4, 5-diaryl-2-[2-alkylthio-5-imidazolyl] imidazole derivatives were synthesized and their anti-inflammatory and anti-nociceptive activities were evaluated on male BALB/c mice [25-30 g]. Molecular modeling and in vitro COX-1 and COX-2 isozyme inhibition studies were also performed. 2-[2-Alkylthio-5-imidazolyl]-4,5-diphenylimidazole compounds were obtained by the reaction of benzyl with 2-alkylthio-1-benzylimidazole-5-carbaldehyde, in the presence of ammonium acetate. Spectroscopic data and elemental analysis of compounds were obtained and their structures elucidated. Anti-nociception effects were examined using writhing test in mice. The effect of the analogues [7.5, 30, 52.5 and 75 mg/kg] against acute inflammation were studied using xylene-induced ear edema test in mice. Celecoxib [75 mg/kg] was used as positive control. All four analogues exhibited anti-nociceptive activity against acetic acid induced writhing, but did not show significant analgesic effect [P< 0.05] compared with celecoxib. It was shown that analogues injected 30 min before xylene application reduced the weight of edematic ears. All analogues were found to have less selectivity for COX-2 in comparison to celecoxib. Injected doses of synthesized analogues possesses favorite anti-nociceptive effect and also has anti-inflammatory effects, but comparing with celecoxib this effect is not significantly different. On the other hand selectivity index for analogues is less than celecoxib and so we expect less cardiovascular side effects for these compounds

Synthesis and effects of novel dihydropyridines as dual calcium channel blocker and angiotensin antagonist on isolated rat aorta

Four novel losartan analogues 5a-d were synthesized by connecting a dihydropyridine nucleus to imidazole ring. The effects of 5a and 5b on angiotensin receptors [AT1] and L-type calcium channels were investigated on isolated rat aorta. Aortic rings were pre-contracted with 1 microM Angiotensin II or 80 mM KC1 and relaxant effects of losartan, nifedipine, 5a and 5b were evaluated by cumulative addition of these drugs to the bath solution. The results showed that compounds 5a and 5b have both L-type calcium channel and AT1 receptor blocking activity. Their effects on AT1 receptors are 1000 and 100, 000 times more than losartan respectively. The activity of compound 5b on L-type calcium channel is significantly less than nifedipine but compound 5a has comparable effect with nifedipine. Finally we concluded that these two new Compounds can be potential candidates to be used as effective antihypertensive agents

Synthesis and calcium channel antagonist activity of 4-[[halobenzyl] imidazolyl] dihydropyridines

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

Effects of 4-[2-Alkylthio-1-benzyl-5-imidazolyl]-dihydropyridines on the isolated rat colon and right atrium contractility

In order to provide a pharmacological profile for some newly synthesized dihydropyridines, we investigated their effects on the isolated rat colon segments and the isolated rat atrium contractility. The tested compounds include alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-alkylthio-1-benzyl-5-imidazolyl substituent, and nifedipine as a positive control substance. Isolated rat colon and atrial tissues were prepared. Rat colon was contracted with 80 mM KC1, and maximum response was recorded [100%]. After washing tissue with Krebs solution it was preincubated with different concentrations of test compounds and again KC1 was added and percent change in contraction was calculated. Spontaneous contractions and its frequency for colon and atrium before and after addition of test compounds were also recorded and percent change was calculated. Nifedipine [10[-8]-10[-5] M] was used as positive control at all experiments. The compounds showed similar effects to that of nifedipine on the isolated rat colon. The potency of these analogues with concentration range 10[-5] to 10[-4] M was compared to potency of nifedipine which was effective at 10[-8] to 10[-5] M [P<0.01]. However, unlike nifedipine, the test compounds exerted significant positive inotropic effect on the isolated rat atrium [P < 0.01]. Our observations suggest that these analogues of nifedipine selectively enhance contractility of heart muscle while causing relaxation of intestinal smooth muscle. These compounds may serve as valuable probes to develop novel dihydropyridines with dual smooth muscle relaxant effect and positive inotropic action