Synthesis And Anticonvulsant Activity Of 8-alkoxy-5, 6-dihydro-4 H-benzo[f][1,2,4] Triazolo [4,3-a][1]azepin Derivatives

Epilepsy is a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In epilepsy, the normal pattern of neuronal activety becomes disturbed causing strange sensations, emotions, and behaviors or sometimes convulsions, muscle spasms, and loss of consciousness. Anticonvulsant drugs are an important part of the treatment program for epilepsy. The maximal elec-troshock (MES) seizure model remains an important first screen and is quite effective in identifying drugs that block human tonic-clonic seizures. This model and the subcutaneous pentylenetetrazol (scPTZ) tests remain the 'gold standards' for the early detection of anticonvulsant activity. Both models are well suited for screening anticonvulsant activity because they do not assume that the pharmacodynamic activity of a particular drug is dependent on the drug's molecular mechanism of action. They can therefore provide insight into the pharmacokinetic-pharmacodynamic relationship of potential new AEDs.Benzazepine derivatives have exhibit broad pharmacological activity. Triazole compounds have wide variety of biological activities, the introduction of triazole ring to some activated molecules may significantly improve the biological activity of the parent molecule due to the superposition of biological activity. Previously, we have reported some 1,3,4,5-tetrahydro-7-alkoxy-2H-1-benzazepin-2-one derivatives as moderately active anticonvulsant agents. In view of these and as a part of our endur-ing studies in the area of anticonvulsant agents it was thought of interest to combine the both pharmacophoric groups (Benzazepine nucleus and triazole ring). We have synthesized a series of 8-alkoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1] azepin derivatives and evaluated for their potential as anticonvulsant agents.A novel series of 8-alkoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1] azepin derivatives were synthesized and characterized by IR,1H NMR,13C NMR, mass. The newly synthesized compounds were screened for their anticonvulsant activities by the maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) test, their neurotoxic effects were determined by the rotarod neurotoxicity test. The result showed that, In the anti-MES potency test,8-pentyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1]azepin (7d) and 8-hexyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1]azepin (7e). was found to be the most potent with ED50 value of 17.5 and 17.7 mg/kg, and had protective index(PI) value of 6.5 and 4.8 respectively. To explain the possible mechanism of anticonvulsant activity, compounds 7a-7o was tested in pentylenetetrazole induced seizures tests. compound 7d was the most active in the scPTZ test, it showed median effective dose (ED5o) of 21.2 mg/kg, median toxicity dose (TD50) of 114.1 mg/kg, and the protective index (PI) of 5.4, which was much greater than ED50 and PI of the prototype drugs phenytoin, carbamazepin, and valproate. Possible structure-activity relationship was discussed.