Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA aminotransferase

Michael D. Clift; Richard B. Silverman

doi:10.1016/j.bmcl.2007.10.060

Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA aminotransferase

Michael D. Clift, Richard B. Silverman^*

^*Corresponding author for this work

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

22 Scopus citations

Abstract

The design, synthesis, and evaluation of novel γ-aminobutyric acid aminotransferase (GABA-AT) inhibitors and inactivators can lead to the discovery of new GABA-related therapeutics. To this end, a series of aromatic amino acid compounds was synthesized to aid in the design of new inhibitors and inactivators of GABA-AT. All compounds were tested as competitive inhibitors of GABA-AT. The amino acids with benzylic amines were also tested as substrates for GABA-AT. It was found that these compounds were all poor competitive inhibitors of GABA-AT, but some were substrates of the enzyme, suggesting their utility as scaffolds for potential GABA-AT mechanism-based inactivators. Computer modeling was used to rationalize the substrate activity of the various compounds.

Original language	English (US)
Pages (from-to)	3122-3125
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2007.10.060
State	Published - May 15 2008

Keywords

Aromatic amino acid
Computer modeling
GABA-AT
Inhibitor
Substrate of GABA-AT
γ-Aminobutyric acid
γ-Aminobutyric acid aminotransferase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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title = "Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA aminotransferase",

abstract = "The design, synthesis, and evaluation of novel γ-aminobutyric acid aminotransferase (GABA-AT) inhibitors and inactivators can lead to the discovery of new GABA-related therapeutics. To this end, a series of aromatic amino acid compounds was synthesized to aid in the design of new inhibitors and inactivators of GABA-AT. All compounds were tested as competitive inhibitors of GABA-AT. The amino acids with benzylic amines were also tested as substrates for GABA-AT. It was found that these compounds were all poor competitive inhibitors of GABA-AT, but some were substrates of the enzyme, suggesting their utility as scaffolds for potential GABA-AT mechanism-based inactivators. Computer modeling was used to rationalize the substrate activity of the various compounds.",

keywords = "Aromatic amino acid, Computer modeling, GABA-AT, Inhibitor, Substrate of GABA-AT, γ-Aminobutyric acid, γ-Aminobutyric acid aminotransferase",

author = "Clift, {Michael D.} and Silverman, {Richard B.}",

note = "Funding Information: The authors are grateful to the National Institutes of Health (GM66132) for financial support of this research. We thank Dr. Haitao Ji for carrying out the computer modeling and Dr. Graham Lawton and Dr. Wenxin Gu for helpful discussions. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.",

year = "2008",

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doi = "10.1016/j.bmcl.2007.10.060",

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AU - Clift, Michael D.

AU - Silverman, Richard B.

N1 - Funding Information: The authors are grateful to the National Institutes of Health (GM66132) for financial support of this research. We thank Dr. Haitao Ji for carrying out the computer modeling and Dr. Graham Lawton and Dr. Wenxin Gu for helpful discussions. Copyright: Copyright 2008 Elsevier B.V., All rights reserved.

PY - 2008/5/15

Y1 - 2008/5/15

N2 - The design, synthesis, and evaluation of novel γ-aminobutyric acid aminotransferase (GABA-AT) inhibitors and inactivators can lead to the discovery of new GABA-related therapeutics. To this end, a series of aromatic amino acid compounds was synthesized to aid in the design of new inhibitors and inactivators of GABA-AT. All compounds were tested as competitive inhibitors of GABA-AT. The amino acids with benzylic amines were also tested as substrates for GABA-AT. It was found that these compounds were all poor competitive inhibitors of GABA-AT, but some were substrates of the enzyme, suggesting their utility as scaffolds for potential GABA-AT mechanism-based inactivators. Computer modeling was used to rationalize the substrate activity of the various compounds.

AB - The design, synthesis, and evaluation of novel γ-aminobutyric acid aminotransferase (GABA-AT) inhibitors and inactivators can lead to the discovery of new GABA-related therapeutics. To this end, a series of aromatic amino acid compounds was synthesized to aid in the design of new inhibitors and inactivators of GABA-AT. All compounds were tested as competitive inhibitors of GABA-AT. The amino acids with benzylic amines were also tested as substrates for GABA-AT. It was found that these compounds were all poor competitive inhibitors of GABA-AT, but some were substrates of the enzyme, suggesting their utility as scaffolds for potential GABA-AT mechanism-based inactivators. Computer modeling was used to rationalize the substrate activity of the various compounds.

KW - Aromatic amino acid

KW - Computer modeling

KW - GABA-AT

KW - Inhibitor

KW - Substrate of GABA-AT

KW - γ-Aminobutyric acid

KW - γ-Aminobutyric acid aminotransferase

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SN - 0960-894X

IS - 10

ER -

Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA aminotransferase

Abstract

Keywords

ASJC Scopus subject areas

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