Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

Abstract

A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha-benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

Pharmacokinetics, brain distribution and plasma protein binding of carbamazepine and nine derivatives: New set of data for predictive in silico ADME models

“…This apparent discrepancy might be explained by the fact that, in vivo, OXC has yielded a metabolite (S-Lic) that is more innocuous than the major metabolite of CBZ. However, the protection conferred by OXC against MESinduced seizures in rats is lower than that obtained after ESL administration (Benes et al, 1999). Considering the results reported herein, this may be due to the fact that ESL is rapidly and extensively metabolized to S-Lic, which bioavailability measured in terms of AUC 0-12h was approximately 6 times greater than that obtained after oral intake of an equimolar dose of OXC (Table 2).…”

“…For instance, CBZ, which is well known for its considerable neurological and motor toxicity in humans ascribed to the metabolite CBZ-E (Myllynen et al, 2002;Spina, 2002), presented the lowest value of effective dose for protecting 50% of the rats (ED 50 ) against MES-induced seizures and the lowest median toxic dose (TD 50 ) in the rotarod test (Ambrósio et al, 2002;Benes et al, 1999;Bonifácio et al, 2001). This means that, at lower concentrations, CBZ develops motor impairment that is not observed for the other compounds and its protective index (given by the ratio between ED 50 and TD 50 ) is considerably lower in relation to OXC, ESL, S-Lic, R-Lic, BIA 2-059 and BIA 2-024 (Benes et al, 1999;Bonifácio et al, 2001;Learmonth et al, 2001). These in vivo pharmacodynamic behaviours are strongly supported by our results which revealed that CBZ was the only dibenz[b,f]azepine-5-carboxamide derivative extensively metabolized to CBZ-E.…”

“…The bioavailability of S-Lic after oral administration of BIA 2-059 to mice was significantly lower than that obtained after ESL or OXC administration. Interestingly, this finding may explain the considerable lower protective index of BIA 2-059 against MES-induced seizures in rats, compared to that of ESL, in spite of their in vitro similar ability to inhibit the sodium uptake into cortical synaptosomes (Benes et al, 1999;Hainzl et al, 2001). …”

“…For instance, in vitro it was demonstrated that BIA 2-024 had a higher potency to bind to sodium channels and modulate sodium entry than CBZ. However, in vivo, it is as effective as CBZ and OXC at controlling seizures (Ambrósio et al, 2001;2002;Benes et al, 1999;Learmonth et al, 2001). Although this may seem contradictory, the low brain-to-plasma ratios herein obtained for BIA 2-024 in relation to those obtained for CBZ and the slower absorption of BIA 2-024 may justify its potency in vivo.…”

Eslicarbazepine Acetate (BIA 2-093)

“…1,2 ESL shares with carbamazepine (CBZ) and oxcarbazepine (OXC) the basic chemical structure of a dibenzazepine nucleus with the 5-carboxamide substituent, but is structurally different at the 10,11-position. 1,2 (FIG. 1).…”