Synthesis and Anticonvulsant Activity of New N‐(Alkyl/Sub‐stituted aryl)‐N′‐[4‐(5‐cyclohexylamino)‐1,3,4‐thiadiazole‐2‐yl)phenyl]thioureas

A series of novel thiourea derivatives carrying the 5‐cylohexylamino‐1,3,4‐thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, ¹H‐NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10 , 11 , 13 , and 14 carrying 2‐methylphenyl, 4‐chlorophenyl, allyl, and 4‐methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED₅₀ values of the active compounds 10 , 11 , 13 , and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.     

哒嗪酮酸类化合物的合成及其抗惊活性的研究

以ａ－酮戊二酸与水合肼与水合肼为原始原料合成了１５个Ｎ－（３’－磷酸二乙酯丙基）－１，６－二氢－６－氧－３－哒嗪酰胺类化合物，并对它们进行了最大电休克发作（ＭＥＳ）实验，结果表明其中４个化合物表现出中等强度的抗惊活性。     

白芍总甙的抗惊厥作用

采用最大电休克发作（ＭＥＳ）法、士的宁惊厥法和戊血氮最小阈发作（ＭＥＴ）法，观察白芍总甙（ＴＧＰ）对动物惊厥的影响。实验结果表明，ＴＧＰ（２０～８０ｍｇ·ｋｇ－１·ｄ－１，ｉｐ和ｉｇ×３ｄ）呈剂量依赖性对抗小鼠的ＭＥＳ。ＴＧＰ（６０～１００ｍｇ·ｋｇ－１·ｄ－１，ｉｐ）能对抗士的宁引起的小鼠和大鼠的惊厥。ＴＧＰ（４０～８０ｍｓ·ｋｇ－１·ｄ－１，ｉｐ）对小鼠的ＭＥＴ无影响。ＴＧＰ（４０～８０ｍｇ·ｋｇ－１·ｄ－１，ｉｐ）对小鼠ＭＥＳ的作用高峰时间在０．５～１．５ｈ之间。     

石菖蒲醇提取物的抗惊厥作用

目的：研究石菖蒲醇提取物的抗惊厥作用。方法：采用最大电休克发作（ＭＥＳ）法,士的宁惊厥法和戊四氮最小阈发作（ＭＥＴ）法,观察石菖蒲醇提取物对动物惊厥的影响。结果;石菖蒲醇提取物能明显对抗大鼠,小鼠的最大电休克发作和小鼠的戊四氮最小阈发作及士的宁的惊厥的反应。结论;石菖蒲醇提取物具有明显的抗惊厥作用。     

Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives

The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n). The bioevaluation demonstrated that most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED(50) value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 4h displayed broad-spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system.     

Synthesis and Evaluation of 3‐[(2,4‐Dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile Derivatives as Potential Anticonvulsants

New 3‐[(2,4‐dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile derivatives 8 – 37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure–activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11 , 18 , 31 , and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two‐electron donor.     

Synthesis of some 3-(arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazole derivatives and their anticonvulsant activity

A series of novel 3-[[(substituted phenyl)methyl]thio]-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazoles 11-20 and several related Schiff's bases, 3-[[(substituted phenyl)-methyl]thio]-4-alkyl/aryl-5-[[[(substituted phenyl/5-nitro-2-furyl)methylene]amino]-phenyl]-4H-1,2,4-triazoles 21-31 were synthesized for evaluation of their biological properties. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. A number of triazole derivatives, exhibited protection after intraperitoneal administration at the dose of 100 and 300 mg/kg in one or both models employed. Compounds 12, 13 and 14 were subjected to oral MES screening in rats at 30 mg/kg and were observed to protect 50% of the animals employed in the experiment. Antimicrobial and antituberculosis activity of these compounds 11-31 were also screened. Some of the tested compounds showed marginal activity against M. tuberculosis H37 Rv.     

Screening of the anticonvulsant activity of some plants from Fabaceae family in experimental seizure models in mice

BACKGROUND AND PURPOSE OF THE STUDY: Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be an advantage in search for safe and effective medicines. In this study the anticonvulsant effect of the leaves of Albizzia julibrissin, Acacia juliflora, Acacia nubica and aerial parts of Astragalus obtusifolius was evaluated in pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure tests. METHODS: The hydroalcoholic extracts of the plants were obtained by percolation. Different doses of the extracts were injected to the mice intraperitoneally (i.p.) and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p.) or tonic seizures induced by MES (50 mA, 50Hz, 1sec) were monitored up to 30 min after administration. Acute toxicity of the extracts was also assessed. The safe and effective extract was then fractionated by dichloromethane and anticonvulsant activity of the fractions was determined. Finally, the constituents of the extract and the fractions were screened by thin layer chromatography. RESULTS: Among the extracts, only A. obtusifolius extract showed low toxicity and protective effect against clonic seizures with ED50 value of 3.97 g/kg. Fractionation of the extract led to increase in anticonvulsant activity and ED50 value of 2.86 g/kg was obtained for the aqueous fraction. Phytochemical screening revealed the presence of alkaloids, flavonoids, anthrones and saponins in the aqueous fraction. MAJOR CONCLUSION: The presence of anticonvulsant compounds in A. obtusifolius suggests further activity-guided fractionation and analytical studies to find out the potential of this plant as a source of anticonvulsant agent.     

Synthesis and Anticonvulsant Activity Evaluation of 5‐Phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amines

In the present study we describe the syntheses and anticonvulsant activity evaluation of 5‐phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amine derivatives. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of these compounds, the most promising was compound 8h , which showed an ED₅₀ value of 27.4 mg/kg and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED₅₀ and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti‐MES efficacy, the potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide were also established, with the results suggesting that the GABAergic system‐mediated mechanisms might be involved in its anticonvulsant activity.     

Inhibition of the action of anticonvulsants by lithium treatment

The present study demonstrates that the effectiveness of anticonvulsants significantly decreases following lithium treatment (3 doses of 50 mg/kg of LiCl given every 12 hr). The anticonvulsant action of phenytoin, phenobarbital and of 3 carbonic anhydrase inhibitors: methazolamide, acetazolamide, ethoxzolamide, was assessed in rats subjected to maximal electroshock. In a chronic study on tolerance development to the anticonvulsant action of acetazolamide, lithium treatment (10 mg/kg per day) has been shown to inhibit gradually the action of acetazolamide. These results are consistent with the hypothesis that norepinephrine and dopamine are involved in the action of anticonvulsants.     

芹菜甲素和乙素的抗惊厥作用

1-芹菜甲素(1-3-丁基苯酞)和1-芹菜乙素(1-3-丁基-4,5二氢苯酞)是从芹菜籽分离出的抗惊厥有效成分。在小于TD₅₀剂量下,对最大电休克(MES),最小电休克(MET),戊四唑(MST)和原发听源性惊厥(MAS)等四种动物模型有效,可认为有广泛的抗惊作用。其人工合成的dl-芹菜甲素(dl-3-丁基苯酞)更有抗惊作用强,毒性小和便于推广应用的优点。     

Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: a comparative study

The aim of this study was to determine and compare the anticonvulsant activities of four natural furanocoumarins [bergapten (5-methoxypsoralen), imperatorin (8-isopentenyloxypsoralen), oxypeucedanin (5-epoxy-isopentenyloxypsoralen) and xanthotoxin (8-methoxypsoralen)] in the maximal electroshock-induced seizure test in mice. The anticonvulsant effects of bergapten, imperatorin, oxypeucedanin, and xanthotoxin were evaluated at 15, 30, 60 and 120 min after their systemic (intraperitoneal) administration. Tonic hind limb extension (seizure activity) was evoked in adult albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. The time courses of protection by bergapten, imperatorin, oxypeucedanin and xanthotoxin against maximal electroshock-induced seizures revealed that 300 mg/kg imperatorin and xanthotoxin (C-8 substituted derivatives of psoralen) exerted strong anticonvulsant activity, whereas 300 mg/kg bergapten and oxypeucedanin (C-5 substituted derivatives of psoralen) did not produce any anticonvulsant activity in this model. In conclusion, imperatorin and xanthotoxin protected the animals against maximal electroshock-induced seizures, whereas bergapten and oxypeucedanin, despite their chemical and structural similarities to xanthotoxin and imperatorin, exerted no anticonvulsant activity in this seizure test.     

Design,Synthesis, and Anticonvulsant Activity Evaluation of 4‐(3‐Alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones

A series of 4‐(3‐alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones were synthesized using the appropriate synthetic route and evaluated experimentally in the maximal electroshock test; their neurotoxicities were evaluated by the rotarod neurotoxicity test. The structures of these compounds were confirmed by IR, MS, ¹H‐NMR, and elementary analysis. All target compounds exhibited anticonvulsant activity to varying degrees in the maximal electroshock test. 4‐(3‐Benzyloxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐one ( 4i ) was the most promising compound with an ED₅₀ value of 30.5 mg/kg and a protective index (PI) of 18.63, showing a higher safety than the standard carbamazepine (PI = 6.45). In addition, the potency of compound 4i against seizures induced by pentylenetetrazole and 3‐mercaptopropionic acid suggested its broad‐spectrum activity, and the mechanisms of action including inhibition of voltage‐gated ion channels and modulation of GABAergic activity might be involved in its anticonvulsant activity.     

Adjuvant role of Ocimum sanctum hydroalcoholic extract with carbamazepine and phenytoin in experimental model of acute seizures

PurposeThis study assessed adjuvant potential of Ocimum sanctum hydroalcoholic extract (OSHE) with antiepileptic drugs (AEDs) carbamazepine (CBZ) and phenytoin (PHT) in maximal electroshock seizure (MES) model in male Wistar rats.Material and MethodsPharmacodynamic effect of OSHE (1000 mg/kg) was assessed through seizure protection potential, neurobehavioral tests and oxidative stress estimation in MES model after 14 days administration of OSHE alone or combination with maximal (M) and sub-maximal (SM) dose of CBZ or PHT. Pharmacokinetic interaction of OSHE with AEDs was also assessed after 14 days of drug treatment.ResultsOSHE per se showed 50% protection against MES-induced seizures. Combination of OSHE with AEDs’ SM dose enhanced its seizure protection potential. Significant reduction in duration of tonic hind limb extension was observed in CBZ-SM + OSHE as compared to control group (p = 0.006). Among neurobehavioral tests in Morris water maze test rats of CBZ-M + OSHE took significantly less time to reach the platform (p = 0.022) and spent more time in target quadrant (p = 0.016) as compared to other groups. Similarly, rats of PHT-SM + OSHE group spent significantly more time in the target quadrant (p = 0.013). In elevated plus maze test, CBZ-M + OSHE had significantly decreased transfer latency compared to other groups (p = 0.013). OSHE alone treated group had significantly lower oxidative stress as compared to other groups. No significant pharmacokinetic interaction was observed between OSHE and AEDs (CBZ, PHT).ConclusionOcimum’s potential of enhanced seizure protection and neuroprotection along with minimal drug interaction with AEDs substantiate its adjuvant role in the management of epilepsy.     

Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study<Superscript>A,B</Superscript>

Combining the use of some antiepileptic drugs (AEDs) in patients with epilepsy can result in interactions of a pharmacodynamic or pharmacokinetic character. To quantify the profile of interactions between tiagabine (TGB) and gabapentin (GBP), two novel AEDs influencing the GABAergic neurotransmitter system, an isobolographic analysis was performed in the maximal electroshock seizure threshold (MEST), pentylenetetrazole (PTZ)-induced seizure and chimney tests in mice. TGB and GBP injected alone dose-dependently raised the electroconvulsive threshold in mice, which allowed the evaluation of TID₂₀ (the dose increasing the threshold by 20% compared with controls) in the MEST-test. TID₂₀ values for TGB and GBP alone were 4.3 mg/kg and 70 mg/kg, respectively. On the basis of isobolographic calculations, TGB was also co-administered with GBP at three fixed ratios (1:3, 1:1 and 3:1) of their respective TID₂₀ doses. The isobolographic analysis showed that all three combinations of TGB with GBP exerted supra-additive (synergistic) interactions in the MEST-test in mice. Likewise, TGB and GBP injected alone suppressed the clonic phase of PTZ-induced seizures, with (effective) doses protecting 50% of the animals tested against clonic convulsions (ED₅₀) for TGB and GBP of 0.9 and 199.3 mg/kg, respectively. Moreover, the two-drug combinations at the same fixed ratios of 1:3, 1:1 and 3:1 in PTZ-induced seizures also showed a tendency towards supra-additive (synergistic) interactions. The adverse (neurotoxic) effects produced by TGB and GBP alone or in combinations at the same fixed ratios of 1:3, 1:1 and 3:1 were evaluated in the chimney test. The (toxic) doses evoking motor impairment in 50% of animals tested (TD₅₀) for TGB and GBP alone were 13.6 and 979.6 mg/kg, respectively. The isobolographic analysis showed the interactions between the AEDs to be additive in this test. From a preclinical point of view, the interactions observed experimentally showed that the combination of TGB and GBP, due to a synergistic anti-seizure activity of the drugs, might provide adequate seizure control in patients with refractory epilepsy.^AThe results of the MEST-test in this study were presented at the 3rd Forum of European Neuroscience, Paris, France, 13–17 July, 2002 (abstract 559).^BThe results of the PTZ-test in this study were presented at the conference: Thirty years of cooperation between German and Polish pharmacologists—new perspectives in the Common Europe, Bialowieza, Poland, 18–21 September, 2003 (abstract: Pol J Pharmacol, 2003, 55:500–501).     

Synthesis of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-ones and evaluation of their anticonvulsant properties

A series of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-one derivatives were synthesized using 7-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and the subcutaneous pentylenetetrazole test (sc-PTZ), and their neurotoxicities were measured by the rotarod neurotoxicity test (Tox). The tests demonstrated that 8-hexyloxy-4,5-dihydro-[1.2.4]triazole[4.3-a]quinoline-1-one (4e) and 8-heptyloxy-4,5-dihydro-[1,2,4] triazole[4,3-a]quinoline-1-one (4f) were the most potent anticonvulsants, with 4e having ED50 values of 17.17 mg/kg and 24.55 mg/kg and protective index (PI = TD50/ED50) values of 41.9 and 29.3 in the MES and sc-PTZ tests, respectively, and 4f having ED50 values of 19.7 mg/kg and 21.2 mg/kg and PI values of 36.5 and 33.9 in the MES and sc-PTZ tests, respectively. The PI values of 4e and 4f were many fold better than that of the marketed drugs phenytoin, carbamazepine, phenobarbital and valproate, which have PI values in the range of 1.6-8.1 in the MES test and < 0.22-5.2 in the sc-PTZ test. Structure-activity relationships were also discussed.     

Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model

The aim of this study was to characterize the pharmacodynamic, pharmacokinetic, and adverse-effect profiles of retigabine (RTG) in combination with carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA). The isobolographic analysis for parallel and nonparallel dose–response effects was used in the mouse maximal electroshock seizure (MES) model for evaluation of pharmacodynamic interaction. Potential adverse-effect profiles of interactions of RTG with CBZ, LTG, and VPA at the fixed ratio of 1:1 in the MES test were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip strength (muscular strength) tests. Free plasma and total brain concentrations of CBZ, LTG, and VPA were determined by immunofluorescence and chromatography to assess pharmacokinetic interaction. In the MES model, RTG administered singly had its dose–response relationship curve (DRRC) parallel to that for VPA and nonparallel to that for CBZ and LTG. With isobolography for parallel DRRCs, the combination of RTG with VPA at fixed ratios of 1:3, 1:1, and 3:1 exerted supraadditive (synergistic) interaction. Isobolography for nonparallel DRRCs revealed that the combinations of RTG with CBZ and LTG at the fixed ratio of 1:1 produced additive interaction. In all combinations, neither motor coordination, long-term memory, nor muscular strength were affected. Only the combination of RTG with VPA at the fixed ratio of 3:1 was complicated by a pharmacokinetic increase in both free plasma and total brain VPA concentrations. All remaining combinations of RTG with VPA, CBZ, and LTG were pharmacodynamic in nature. RTG synergistically interacted with VPA and exerted additive interaction with CBZ and LTG in the mouse MES model.     

Synthesis and Anticonvulsant Activity of N‐(2‐Hydroxy‐ethyl)amide Derivatives

A series novel of N‐(2‐hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N‐(2‐hydroxyethyl)decanamide 1g , N‐(2‐hydroxyethyl)palmitamide 1l , and N‐(2‐hydroxyeth‐yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti‐epileptic drug valproate. In the anti‐MES potency test, these compounds exhibited median effective doses (ED₅₀) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD₅₀) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti‐epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g , 1l , and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3‐mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.