Journal
CURRENT MEDICINAL CHEMISTRY
Volume 12, Issue 18, Pages 2041-2056Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929867054637635
Keywords
synaptic vesicle; glutarnate; inhibitor; pharmacophore; transporter; VGLUT
Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR015583] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS042077, R01NS038248, R15NS039814] Funding Source: NIH RePORTER
- NCRR NIH HHS [P20 RR15583] Funding Source: Medline
- NINDS NIH HHS [R15 NS39814, 1 R21 NS042077, R01 NS-38248] Funding Source: Medline
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The vesicular glutamate transporter (VGLUT) is responsible for the uptake of the excitatory amino acid, L-glutamate, into synaptic vesicles. VGLUT activity is coupled to an electrochemical gradient driven by a vacuolar ATPase and stimulated by low C1. VGLUT has relatively low affinity (K-m = 1-3 mM) for glutamate and is pharmacologically and structurally distinct from the Na+-dependent, excitatory amino acid transporters (EAATs) found on the plasma membrane. Because glutamatergic neurotransmission begins with vesicular release, compounds that block the uptake of glutamate into the vesicle may reduce excitotoxic events. Several classes of competitive VGLUT inhibitors have emerged including amino acids and amino acid analogs, fatty acids, azo dyes, quinolines and alkaloids. The potency with which these agents inhibit VGLUT varies from millimolar (amino acids) to nanomolar (azo dyes) concentrations. These inhibitors represent highly diverse structures and have collectively begun to reveal key pharmacophore elements that may elucidate the key interactions important to binding VGLUT. Using known inhibitor structures and preliminary molecular modeling, a VGLUT pharmacophore is presented that will aid in the design of new, highly potent and selective agents.
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