Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate

Jong M. Rho, Sean D. Donevan, Michael A Rogawski

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Felbamate and meprobamate are structurally related propanediol dicarbamates that possess distinct pharmacological profiles. Felbamate is a minimally sedative, broad-spectrum anticonvulsant, whereas meprobamate is a strong sedative-anxiolytic agent. Previously, we reported that felbamate potentiates γ-aminobutyric acid(A) (GABA(A)) receptor Cl- currents and inhibits N-methyl-D-aspartate (NMDA) receptor currents. Here we further characterized the interaction of the two dicarbamates with 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), exhibited a separate channel-blocking effect that limited the magnitude of GABA(A) receptor potentiation. At equivalent concentrations, meprobamate 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 deactivation time constant of whole-cell currents evoked by 10 mM meprobamate (110 ms) or 1 and 3μM 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 mean burst duration of GABA-activated unitary currents in excised outside-out membrane patches. In addition, at high (supratherapeutic) concentrations, meprobamate blocked NMDA-activatad currents. We conclude that felbamate and meprobamate have barbiturate-like modulatory actions on GABA(A) receptors, but meprobamate has greater activity and, unlike falbamate, is able to directly activate the receptor.

Original languageEnglish (US)
Pages (from-to)1383-1391
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume280
Issue number3
StatePublished - Mar 1997
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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