ANTICONVULSANT ACTIVITY AND INTERACTIONS WITH NEURONAL VOLTAGE-DEPENDENT SODIUM-CHANNEL OF ANALOGS OF AMELTOLIDE

Fifteen compounds related to ameltolide (LY 201116) were studied for ( i) anticonvulsant potential in the maximal electroshock-induced seizur es (MES) and the subcutaneous pentylenetetrazol (sc Ptz) tests in mice and rats and (ii) interactions with neuronal voltage-dependent sodium channels. Compounds were chosen ranging in anticonvulsant activity in mice from very active to inactive. The active compounds were defined as those protecting 50% of the animals at doses between 10 and 50 mu m ol/kg and inactive compounds as those protecting 50% of the animals at doses greater than 1 mmol/kg. The series studied included three N-(2, 6-dimethylphenyl)benzamides (compounds 1, 2 (ameltolide), and 3), thre e N-(2,2,6,6-tetramethyl)piperidinyl-4-benzamides (compounds 4, 5, 6), one phenylthiourea (compound 7), five N-(2,6-dimethylphenyl)phthalimi des (compounds 8, 9, 10, 13, and 14), two N-phenylphthalimide derivati ves (compounds 11 and 12), and one N-(2,2,6,6-tetramethyl)piperidinyl- 4-phtalimide (compound 15). Phenytoin (PHT) was employed as the refere nce prototype antiepileptic drug. After inital screening in mice, comp ounds 1, 2, 3, 5, 8, 9, 10, 13, and 14 were selected for further testi ng in rats. Anticonvulsant ED(50)s (effective doses in at least 50% of animals tested) of compounds in the MES test were determined in rats dosed orally and amounted to 52 (1), 135 (2), 284 (3), 31 (8), 131 (9) , 25 (10), 369 (13), 354 (14), and 121 (PHT) mu mol/kg, compound 5 pre senting with an ED50 value higher than 650 mu mol/kg. In our hands, th e apparent IC(50)s (inhibitory concentrations 50) of compounds toward binding to rat brain synaptosomes of [H-3]batrachotoxinin-A-20 alpha-b enzoate were 0.25 (1), 0.97 (2), 0.35 (3), 25.8 (5), 161.3 (8), 183.5 (9), 0.11 (10), 1.86 (13), 47.8 (14), and 0.86 (PHT) mu M. The relatio nship between the activity in the MES test and the capacity to interac t in vitro with neuronal voltage-dependent sodium channels and the fac t that the IC50 values obtained in the in vitro test are close to the brain concentrations at which anticonvulsant activities are reported t o occur for ameltolide strongly suggest that the anticonvulsant proper ties of most compounds tested could be a direct result of their intera ction with the neuronal voltage-dependent sodium channel.