1: J Med Chem 1998 Aug 27;41(18):3307-13
Anticonvulsant activity and interactions with neuronal voltage-dependent
sodium channel of analogues of ameltolide.
Vamecq J, Lambert D, Poupaert JH, Masereel B, Stables JP
INSERM/CHRU Lille, Domaine du Certia, 369 rue Jules Guesde, BP 39, 59651
Villeneuve d'Ascq Cedex, France.
Fifteen compounds related to ameltolide (LY 201116) were studied for (i)
anticonvulsant potential in the maximal electroshock-induced seizures (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 micromol/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), three N-(2,2,6, 6-tetramethyl)piperidinyl-4-benzamides
(compounds 4, 5, 6), one phenylthiourea (compound 7), five N-(2,6-dimethylphenyl)phthalimides
(compounds 8, 9, 10, 13, and 14), two N-phenylphthalimide derivatives (compounds
11 and 12), and one N-(2,2,6, 6-tetramethyl)piperidinyl-4-phthalimide (compound
15). Phenytoin (PHT) was employed as the reference prototype antiepileptic
drug. After inital screening in mice, compounds 1, 2, 3, 5, 8, 9, 10, 13,
and 14 were selected for further testing in rats. Anticonvulsant ED50s
(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), 231 (8), 131 (9), 25 (10), 369 (13), 354 (14), and 121 (PHT)
micromol/kg, compound 5 presenting with an ED50 value higher than 650 micromol/kg.
In our hands, the apparent IC50s (inhibitory concentrations 50) of compounds
toward binding to rat brain synaptosomes of [3H]batrachotoxinin-A-20alpha-benzoate
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) microM. The relationship between
the activity in the MES test and the capacity to interact in vitro with
neuronal voltage-dependent sodium channels and the fact that the IC50 values
obtained in the in vitro test are close to the brain concentrations at
which anticonvulsant activities are reported to occur for ameltolide strongly
suggest that the anticonvulsant properties of most compounds tested could
be a direct result of their interaction with the neuronal voltage-dependent
sodium channel.
PMID: 9719582, UI: 98387858