Anticonvulsant activities of phenyl-substituted bicyclic 2,4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel

Abstract

8,9-Dioxo-6-phenyl-1-aza-7-oxabicyclo[4.2.1]nonane (1) and 9,10-dioxo-7-phenyl-1-aza-8-oxabicyclo[5.2.1]decane (2), examples of anti-Bredt bicyclic 2,4-oxazolidinediones, were investigated as anticonvulsants in mice. Compound 2 was the more potent (anti-MES ED50 = 66 mg/kg), and its in vivo anti-MES effect was consistent with its in vitro potency of binding to the voltage-sensitive sodium channel (IC50 = 160 microM for the inhibition of binding of [3H]BTX-B), suggesting that 2 may be a new class I anticonvulsant. Several partial structures of 2, either monocyclic lactams or monocyclic 2,4-oxazolidinediones, were also evaluated in these assays, but no correlation was observed between sodium channel binding and anti-MES effects. A significant finding was that monocyclic 5-alkyl-5-phenyl-2,4-oxazolidinediones provided relatively potent, nontoxic, broad-spectrum anticonvulsants.

Sodium Channel Binding and Anticonvulsant Activities of Hydantoins Containing Conformationally Constrained 5-Phenyl Substituents

“…10 Biology-Hydantoins 1-4,6, and 7 were each evaluated in synaptoneurosomal preparations from rat cerebral cortex as inhibitors of the specific binding of [3Hlbatrachotoxinin A 20-a-benzoate (L3H]BTX-B) to the voltage-sensitive sodium channel according to our previously reported procedure. 3 The percent inhibition values were initially obtained at a single concentration (either 250 or 500 pM). The IC,, values for the more active compounds were then determined from d o s c response curves.…”

“…As shown in Table I, 3 was a poor binder to the sodium channel. However, the anti-MES activity for 3, while less than that of 1 and 4, was better than anticipated based on the sodium channel binding data.…”

“…The ICs0 values for the more potent compounds were determined from a dose-response curve as previously described. 3 Anticonvulsant Assays-All whole animal anticonvulsant and neurotoxicity assays were conducted by the Anticonvulsant Drug Development Program of the Epilepsy Branch, National Institute of Neurological Disorders and Stroke. In Phases 1 and 2, compounds were injected intraperitoneally into mice as suspensions in 0.5% methylcellulose.…”

8-Oxa-1-aza-7-phenylbicyclo[5.2.1]decane-9,10-dione

“…Bicyclic imides with a bridgehead N atom were proposed by Smissman as potential stereoselective anticonvulsants (Smissman et al, 1964) and the synthesis of the first examples of this class of compounds (nicknamed `smissmanones′) was reported in 1984 (Brouillette & Einspahr, 1984). The title compound, (I), has significant biological activity and acts as a good antimaximal electroshock anticonvulsant as well as a relatively good binder to a sodium channel (Brouillette et al, 1988). The crystal structure of 1-aza-8,9-dioxo-7-oxa-6-phenylbicyclo[4.2.1]nonane was reported earlier (Brouillette & Einspahr, 1984).…”

Modulation of Sodium Channel Inactivation Gating by a Novel Lactam: Implications for Seizure Suppression in Chronic Limbic Epilepsy

“…Lactams have been shown to displace [ 3 H]batrachotoxinin A 20-␣-benzoate binding from rat brain cerebral cortex synaptosomes, suggesting that they share the same binding site as many clinically used AEDs (Brouillette et al, 1988;Clare et al, 2000). Here, we have compared the actions of YWI92 Development of inactivation was assessed using a two-pulse protocol.…”