title: Inhibitor of the glutamate vesicular transporter (VGLUT).
abstract: 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 Cl-. 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.
authors.affiliation: The Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, USA. charles.thompson@umontana.edu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Erin
authors.initials: E
authors.lastname: Davis
authors.forename: Christina N
authors.initials: CN
authors.lastname: Carrigan
authors.forename: Holly D
authors.initials: HD
authors.lastname: Cox
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bridges
authors.forename: John M
authors.initials: JM
authors.lastname: Gerdes
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D050496:Vesicular Glutamate Transport Proteins
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D018691:Excitatory Amino Acid Antagonists; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C493476:SLC17A6 protein, human; C493464:SLC17A7 protein, human; C460879:SLC17A8 protein, human; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D050496:Vesicular Glutamate Transport Proteins