BARBITURATE-LIKE ACTIONS OF THE PROPANEDIOL DICARBAMATES FELBAMATE AND MEPROBAMATE

Felbamate and meprobamate are structurally related propanediol dicarba mates that possess distinct pharmacological profiles. Felbamate is a m inimally sedative, broad-spectrum anticonvulsant, whereas meprobamate is a strong sedative-anxiolytic agent. Previously, we reported that fe lbamate potentiates gamma-aminobutyric acid(A) (GABA(A)) receptor Cl- currents and inhibits N-methyl-D-aspartate (NMDA) receptor currents. H ere we further characterized the interaction of the two dicarbamates w ith GABA(A) receptors to determine the basis for their pharmacological differences, In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, meprobamate enhanced GABA-evoked responses in a concentration-dependent manner and, at high concentrations (>1 mM), ex hibited a separate channel-blocking effect that limited the magnitude of GABA(A) receptor potentiation. At equivalent concentrations, meprob amate produced substantially greater potentiation than did felbamate. Furthermore, meprobamate (but not felbamate), in the absence of GABA, directly activated Cl- currents that could be attenuated by the GABA(A ) receptor antagonists bicuculline and picrotoxin. The mean deactivati on time constant of whole-cell currents evoked by 10 mM meprobamate (1 10 ms) or 1 and 3 mu M GABA (180 ms) were faster than the deactivation time constant of 10 mM meprobamate (490 ms) or 3 mM felbamate (470 ms ) in the presence of GABA. Meprobamate and felbamate prolonged the mea n burst duration of GABA-activated unitary currents in excised outside -out membrane patches, In addition, at high (supratherapeutic) concent rations, meprobamate blocked NMDA-activated currents. We conclude that felbamate and meprobamate have barbiturate-like modulatory actions on GABA(A) receptors, but meprobamate has greater activity and, unlike f elbamate, is able to directly activate the receptor.