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 acidA(GABAA) receptor Cl− currents and inhibits N-methyl-d-aspartate (NMDA) receptor currents. Here we further characterized the interaction of the two dicarbamates with GABAA 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 GABAA 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 GABAA receptor antagonists bicuculline and picrotoxin. The mean deactivation time constant of whole-cell currents evoked by 10 mM meprobamate (110 ms) or 1 and 3 μM 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-activated currents. We conclude that felbamate and meprobamate have barbiturate-like modulatory actions on GABAA receptors, but meprobamate has greater activity and, unlike felbamate, is able to directly activate the receptor.
Footnotes
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Send reprint requests to: Michael A. Rogawski, M.D., Ph.D., Neuronal Excitability Section, NINDS, NIH, Building 10, Room 5N-250, 10 Center Drive MSC 1408, Bethesda, MD 20892-1408.
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↵1 Present address: Department of Neurology, Children’s Hospital and Medical Center, University of Washington School of Medicine, Seattle, WA 98105, U.S.A.
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↵2 Present address: Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112, U.S.A.
- Abbreviations:
- GABA
- γ-aminobutyric acid
- NMDA
- N-methyl-d-aspartate
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- EGTA
- ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid..
- Received August 23, 1996.
- Accepted November 26, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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