Synthesis and Anticonvulsant Activity of 3-(alkylamino, alkoxy)-1,3,4,5- Tetrahydro-2H-benzo [b] azepine-2-one Derivatives

Background & Objective: A series of novel 3-Substituted-1,3,4,5-Tetrahydro-2H-benzo [b] azepine-2-one Derivatives (4, 5, 7, 10, 12, 5a-j, 8a-e) were synthesized from 1,2,3,4-Tetrahydro-1- naphthalenone. The structures of these compounds were confirmed by IR, 1H NMR, 13C NMR, MASS spectra and elemental analysis. Their anticonvulsant activity was evaluated by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test. Compound 4 showed the maximum anticonvulsant activity against the maximal electroshock test (ED50=26.4, PI =3.2) and against the subcutaneous pentylenetetrazol test (ED50=40.2, PI =2.1). Conclusion: Possible structure-activity relationship was discussed.

Experimental assessment of 2-oxyindolin-3-glyoxylic acid derivative anticonvulsant effect

Aim. To explore the anticonvulsant effect of 2-oxyindolin-3-glyoxylic acid derivative on the model of acute myoclonic seizures caused by pentylenetetrazol, picrotoxin and thiosemicarbazide.Methods. Median effective dose (ED50) of 2-hydro-N-naphthalene-1-yl-2-(2-oxy-1,2-dyhydro-indole-3-ylidene)-acetamide diethyl ether was determined by the maximal electroshock test in experiments on adult Wistar rats of both gender. The effect of median effective dose prophylactic administration of the study medication and comparators - diazepam and sodium valproate - on chemo-induced epileptogenesis was explored. Introduction of proconvulsant drugs (pentylenetetrazol, picrotoxin and thiosemicarbazide) was accompanied by the development of seizures, which was estimated by the intensity of seizures (points), latent period of seizures onset (seconds), the number of convulsive attacks, seizures, duration (seconds) and the number of survived animals in each group.Results. Median effective dose of 2-oxyindolin derivative was 12 mg/kg as measured by maximal electroshock test. This dose of the test compound, similar to diazepam, effectively reduced the severity of seizures caused by pentylenetetrazol, seen as the increased duration of latent period before the seizures onset by 1.9 times, decreased severity of seizures by 1.7 times, decreased number of seizures by 2.1 times, and decreased seizure duration by 2.3 times together with lower mortality. The prophylactic administration of the substance has extended the latent period of seizures by 2.0 times, significantly reduced the number, intensity and duration of seizures, decreased the mortality after administration of picrotoxin. Also, 2-oxyindolin derivative significantly increased the latent period of seizures onset and reduced the severity of seizures due to thiosemicarbazide. At that, the study substance was not inferior in anticonvulsant activity compared to the diazepam as the reference drug.Conclusion. The dose of 12 mg/kg of 2-hydro-N-naphthalene-1-yl-2-(2-oxy-1,2-dyhydro-indole-3-ylidene)-acetamide was effective in preventing seizures associated with gamma-aminobutyric acid (GABA)-convulsants.

Anticonvulsant Effect of Antiaris toxicaria (Pers.) Lesch. (Moraceae) Aqueous Extract in Rodents

Antiaris toxicaria (Moraceae) was evaluated for anticonvulsant activity in rodents. Animal models used include maximal electroshock test (MEST); pentylenetetrazole-induced (PTZ) convulsions; picrotoxin-induced (PCT) convulsions; strychnine- (STR-) and 4-aminopyridine-induced convulsions. Increase in latency to seizures as well as reduction in duration and frequency of seizures indicated anticonvulsant activity. The extract was more effective in all models used except the maximal electroshock test and strychnine-induced convulsions. Antiaris toxicaria aqueous extract (200, 400, and 800 mg kg−1) significantly () shortened the duration of convulsions in PTZ- and PCT-induced seizures. Delay in the onset of convulsions in the two tests was significant (). Reduction in the frequency of seizures was also significant () in both tests. Antiaris further delayed the onset of seizures in 4-aminopyridine model while producing 75% protection against death in mice. Diazepam (0.1, 0.3, and 1 mg kg−1), carbamazepine (3, 10, and 30 mg kg−1), and sodium valproate (100–400 mg kg−1) were used as reference anticonvulsant drugs for various models. Flumazenil blocked the effect of the extract in the PTZ test significantly suggesting that Antiaris toxicaria may be acting by enhancing the effects of the GABAergic system. Antiaris toxicaria aqueous extract therefore possesses anticonvulsant activity.