Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT)

Quinoline-2,4-dicarboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X 1X 2EF and X 1X 2EW tetrapeptides were sy...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (18), p.5125-5128
Main Authors: Patel, Sarjubhai A., Nagy, Jon O., Bolstad, Erin D., Gerdes, John M., Thompson, Charles M.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Glutamate
Glutamatergic system (aspartate and other excitatory aminoacids)
Inhibitor
Medical sciences
Models, Molecular
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Tetrapeptides
Trypan blue
Uptake
Vesicle
Vesicular glutamate transporter (VGLUT)
Vesicular Inhibitory Amino Acid Transport Proteins - antagonists & inhibitors
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Summary:Quinoline-2,4-dicarboxylic acids (QDCs) bearing lipophilic substituents in the 6- or 7-position were shown to be inhibitors of the glutamate vesicular transporter (VGLUT). Using the arrangement of the QDC lipophilic substituents as a template, libraries of X 1X 2EF and X 1X 2EW tetrapeptides were synthesized and tested as VGLUT inhibitors. The peptides QIEW and WNEF were found to be the most potent. Further stereochemical deconvolution of these two peptides showed dQ lI dE lW to be the best inhibitor ( K i = 828 ± 252 μM). Modeling and overlay of the tetrapeptide inhibitors with the existing pharmacophore showed that H-bonding and lipophilic residues are important for VGLUT binding.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.07.006