title: Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system x(c)(-).
abstract: Evidence was acquired prior to suggest that the vesicular glutamate transporter (VGLUT) but not other glutamate transporters were inhibited by structures containing a weakly basic α-amino group. To test this hypothesis, a series of analogs using a hydantoin (pK(a)∼9.1) isostere were synthesized and analyzed as inhibitors of VGLUT and the obligate cystine-glutamate transporter (system x(c)(-)). Of the hydantoin analogs tested, a thiophene-5-carboxaldehyde analog 2l and a bis-hydantoin 4b were relatively strong inhibitors of VGLUT reducing uptake to less than 6% of control at 5mM but few inhibited system x(c)(-) greater than 50% of control. The benzene-2,4-disulfonic acid analog 2b and p-diaminobenzene analog 2e were also good hydantoin-based inhibitors of VGLUT reducing uptake by 11% and 23% of control, respectively, but neither analog was effective as a system x(c)(-) inhibitor. In sum, a hydantoin isostere adds the requisite chemical properties needed to produce selective inhibitors of VGLUT.
authors.affiliation: Core Laboratory for Neuromolecular Production, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, USA.
authors.forename: S Kaleem
authors.initials: SK
authors.lastname: Ahmed
authors.forename: Jean-Louis G
authors.initials: JL
authors.lastname: Etoga
authors.forename: Sarjubhai A
authors.initials: SA
authors.lastname: Patel
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bridges
authors.forename: Charles M
authors.initials: CM
authors.lastname: Thompson
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050496:Vesicular Glutamate Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D006827:Hydantoins; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid