In vitro and in vivo effects on brain GABA metabolism of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based inactivator of γ-aminobutyric acid transaminase

Richard B. Silverman; A. Jabbar Muztar; Mark A. Levy; James D. Hirsch

doi:10.1016/0024-3205(83)90391-0

In vitro and in vivo effects on brain GABA metabolism of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based inactivator of γ-aminobutyric acid transaminase

Richard B. Silverman^*, A. Jabbar Muztar, Mark A. Levy, James D. Hirsch

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The effects of intraperitoneal administration of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based covalent inactivator of γ-aminobutyric acid transaminase (GABA-T), on whole brain GABA metabolism in mice were investigated. A dose-dependent and time-dependent irreversible inactivation of GABA-T was observed with a concomitant increase in whole brain GABA levels. The compound exhibited no in vitro nor in vivo time-dependent inhibition of glutamate decarboxylase (GAD), alanine transaminase, or aspartate transaminase (Asp-T). It was, however, a potent competitive reversible inhibitor of GAD and a weak competitive inhibitor of Asp-T. The chloro analogue, (S)-4-amino-5-chloropentanoic acid, was ineffective.

Original language	English (US)
Pages (from-to)	2717-2723
Number of pages	7
Journal	Life Sciences
Volume	32
Issue number	24
DOIs	https://doi.org/10.1016/0024-3205(83)90391-0
State	Published - Jun 13 1983

Funding

We thank Paul Sumner for determining the mouse brain GABA concentrations and the National Institutes of Health (Grant NS 15703) for financial support of this work.

ASJC Scopus subject areas

General Pharmacology, Toxicology and Pharmaceutics
General Biochemistry, Genetics and Molecular Biology

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@article{2af928e8ef06404682d9dd1ac55c3b8b,

title = "In vitro and in vivo effects on brain GABA metabolism of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based inactivator of γ-aminobutyric acid transaminase",

abstract = "The effects of intraperitoneal administration of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based covalent inactivator of γ-aminobutyric acid transaminase (GABA-T), on whole brain GABA metabolism in mice were investigated. A dose-dependent and time-dependent irreversible inactivation of GABA-T was observed with a concomitant increase in whole brain GABA levels. The compound exhibited no in vitro nor in vivo time-dependent inhibition of glutamate decarboxylase (GAD), alanine transaminase, or aspartate transaminase (Asp-T). It was, however, a potent competitive reversible inhibitor of GAD and a weak competitive inhibitor of Asp-T. The chloro analogue, (S)-4-amino-5-chloropentanoic acid, was ineffective.",

author = "Silverman, {Richard B.} and {Jabbar Muztar}, A. and Levy, {Mark A.} and Hirsch, {James D.}",

note = "Funding Information: We thank Paul Sumner for determining the mouse brain GABA concentrations and the National Institutes of Health (Grant NS 15703) for financial support of this work.",

year = "1983",

month = jun,

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doi = "10.1016/0024-3205(83)90391-0",

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AU - Silverman, Richard B.

AU - Jabbar Muztar, A.

AU - Levy, Mark A.

AU - Hirsch, James D.

N1 - Funding Information: We thank Paul Sumner for determining the mouse brain GABA concentrations and the National Institutes of Health (Grant NS 15703) for financial support of this work.

PY - 1983/6/13

Y1 - 1983/6/13

N2 - The effects of intraperitoneal administration of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based covalent inactivator of γ-aminobutyric acid transaminase (GABA-T), on whole brain GABA metabolism in mice were investigated. A dose-dependent and time-dependent irreversible inactivation of GABA-T was observed with a concomitant increase in whole brain GABA levels. The compound exhibited no in vitro nor in vivo time-dependent inhibition of glutamate decarboxylase (GAD), alanine transaminase, or aspartate transaminase (Asp-T). It was, however, a potent competitive reversible inhibitor of GAD and a weak competitive inhibitor of Asp-T. The chloro analogue, (S)-4-amino-5-chloropentanoic acid, was ineffective.

AB - The effects of intraperitoneal administration of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based covalent inactivator of γ-aminobutyric acid transaminase (GABA-T), on whole brain GABA metabolism in mice were investigated. A dose-dependent and time-dependent irreversible inactivation of GABA-T was observed with a concomitant increase in whole brain GABA levels. The compound exhibited no in vitro nor in vivo time-dependent inhibition of glutamate decarboxylase (GAD), alanine transaminase, or aspartate transaminase (Asp-T). It was, however, a potent competitive reversible inhibitor of GAD and a weak competitive inhibitor of Asp-T. The chloro analogue, (S)-4-amino-5-chloropentanoic acid, was ineffective.

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In vitro and in vivo effects on brain GABA metabolism of (S)-4-amino-5-fluoropentanoic acid, a mechanism-based inactivator of γ-aminobutyric acid transaminase

Abstract

Funding

ASJC Scopus subject areas

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