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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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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,

day = "13",

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

language = "English (US)",

volume = "32",

pages = "2717--2723",

journal = "Life Sciences",

issn = "0024-3205",

publisher = "Elsevier Inc.",

number = "24",

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TY - JOUR

T1 - 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

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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U2 - 10.1016/0024-3205(83)90391-0

DO - 10.1016/0024-3205(83)90391-0

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AN - SCOPUS:0020597703

SN - 0024-3205

VL - 32

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JO - Life Sciences

JF - Life Sciences

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ER -

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

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