Abstract
This study we describe the synthesis of a novel structure of anticonvulsant agent as 6,8-dimethoxy-3-methyl-1,2,3,4- tetrahydroisoquinoline by using GYKI52466, which was the potent anticonvulsant agent, as the lead molecule. Com-pound IV was synthesized and anticonvulsant effects was evaluated against Pentylenetetrazole (PTZ)-induced seizure model in mice. The acute anticonvulsant effect was tested with a single dose of 25 and 75 µmol/kg of the synthesis compound. Sodium valproate and normal saline were used as the reference standard and control, respectively. All compounds were injected intraperitoneally to each mouse an hour prior to seizure induced by injection of 60 mg/kg PTZ and observed their behavior for 30 minutes. The result showed that the IV at 75 µmol/kg could delay the latency to first twitch and decrease percent mortality compared to control group.
Highlights
Epilepsy is a common chronic neurological disorder affecting individuals of all ages
This study we describe the synthesis of a novel structure of anticonvulsant agent as 6,8-dimethoxy-3-methyl-1,2,3,4tetrahydroisoquinoline by using GYKI52466, which was the potent anticonvulsant agent, as the lead molecule
There are several ways for the treatment of epilepsies, antiepileptic drugs (AEDs) remain the most widely utilized treatment [2]. 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3benzodiazepine (GYKI52466, 1) is the first compound showed anticonvulsant that act via noncompetitive-AMPA receptor antagonist and was used as a lead for many studies [3,4,5,6,7,8,9,10]
Summary
Epilepsy is a common chronic neurological disorder affecting individuals of all ages. It is defined as the occurrence of at least one epileptic seizure, unprovoked by any immediate identified cause [1]. According to 3D-pharmacophore study of Barreca et al [11] the simple replacement of diazepine ring with tetrahydropyridine system directed the synthesis toward the 2-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (4), which mapped well onto the 3D-pharmacophore hypothesis (two hydrophobic groups, hydrogen bond acceptor feature and one aromatic region in a specific three-dimensional arrangement) and shows an anti-. Br) at 4’-position on phenyl ring appears to improve the anticonvulsant activity [15,16,17]. We introduce Cl at 4’-position on phenyl ring in expected to improve pharmacological and pharmacokinetic of the compound. The aims are to explore if these modification could influent the anticonvulsant effect by primary screen anticonvulsant activity via Pentylenetetrazole (PTZ)-induced seizure model
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