Syntheses of optically pure beta-hydroxyaspartate derivatives as glutamate transporter blockers.
DL-threo-beta-benzyloxyaspartate (DL-TBOA) is a non-transportable blocker of the glutamate transporters that serves as an indispensable tool for the investigation of the physiological roles of the transporters. To examine the precise interaction between a blocker and the transporters, we synthesized the optically pure isomers (L- and D-TBOA) and its erythro-isomers. L-TBOA is the most potent blocker for the human excitatory amino acid transporters (EAAT1-3), while D-TBOA revealed a difference in the pharmacophores between EAAT1 and EAAT3. We also synthesized the substituent variants (methyl or naphthylmethyl derivatives) of L-TBOA. The results obtained here suggest that bulky substituents are crucial for non-transportable blockers.
Shimamoto
K
K
Suntory Institute for Bioorganic Research, Wakayamadai, Mishima, Osaka, Japan. shimamot@sunbor.or.jp
Shigeri
Y
Y
Yasuda-Kamatani
Y
Y
Lebrun
B
B
Yumoto
N
N
Nakajima
T
T
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D019556:COS Cells; D006224:Cricetinae; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D017470:Receptors, Glutamate; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid