Syntheses of optically pure β-hydroxyaspartate derivatives as glutamate transporter blockers

被引：102

作者：

Shimamoto, K ^{[1
]}

Shigeri, Y

Yasuda-Kamatani, Y

Lebrun, B

Yumoto, N

Nakajima, T

机构：

[1] Suntory Inst Bioorgan Res, Osaka 6188503, Japan

[2] MITI, AIST, Osaka Natl Res Inst, Osaka 5638577, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2000年 / 10卷 / 21期

关键词：

D O I：

10.1016/S0960-894X(00)00487-X

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (EAATI-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. (C) 2000 Elsevier Science Ltd. All rights reserved.

引用

收藏

页码：2407 / 2410

页数：4

相关论文

共 16 条

[1] Physiological and pathological operation of glutamate transporters [J].

Billups, B ;

Rossi, D ;

Oshima, T ;

Warr, O ;

Takahashi, M ;

Sarantis, M ;

Szatkowski, M ;

Attwell, D .

GLUTAMATE SYNAPSE AS A THERAPEUTICAL TARGET: MOLECULAR ORGANIZATION AND PATHOLOGY OF THE GLUTAMATE SYNAPSE, 1998, 116 :45-57

[2]

Bridges RJ, 1999, CURR PHARM DESIGN, V5, P363

[3] CONFORMATIONALLY RESTRICTED INHIBITORS OF THE HIGH-AFFINITY L-GLUTAMATE TRANSPORTER [J].

BRIDGES, RJ ;

LOVERING, FE ;

HUMPHREY, JM ;

STANLEY, MS ;

BLAKELY, TN ;

CRISTOFARO, MF ;

CHAMBERLIN, AR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1993, 3 (01) :115-&

[4] A CONFORMATIONALLY CONSTRAINED COMPETITIVE INHIBITOR OF THE SODIUM-DEPENDENT GLUTAMATE TRANSPORTER IN FOREBRAIN SYNAPTOSOMES - L-ANTI-ENDO-3,4-METHANOPYRROLIDINE DICARBOXYLATE [J].

BRIDGES, RJ ;

LOVERING, FE ;

KOCH, H ;

COTMAN, CW ;

CHAMBERLIN, AR .

NEUROSCIENCE LETTERS, 1994, 174 (02) :193-197

[5] CONFORMATIONALLY DEFINED NEUROTRANSMITTER ANALOGS - SELECTIVE-INHIBITION OF GLUTAMATE UPTAKE BY ONE PYRROLIDINE-2,4-DICARBOXYLATE DIASTEREOMER [J].

BRIDGES, RJ ;

STANLEY, MS ;

ANDERSON, MW ;

COTMAN, CW ;

CHAMBERLIN, AR .

JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (02) :717-725

[6] DIASTEREOSELECTIVE ADDITION OF VINYL ORGANOMETALLIC REAGENTS TO L-SERINAL [J].

COLEMAN, RS ;

CARPENTER, AJ .

TETRAHEDRON LETTERS, 1992, 33 (13) :1697-1700

[7] Properties and localization of glutamate transporters [J].

Danbolt, NC ;

Chaudhry, FA ;

Dehnes, Y ;

Lehre, KP ;

Levy, LM ;

Ullensvang, K ;

Storm-Mathisen, J .

GLUTAMATE SYNAPSE AS A THERAPEUTICAL TARGET: MOLECULAR ORGANIZATION AND PATHOLOGY OF THE GLUTAMATE SYNAPSE, 1998, 116 :23-43

[8]

Esslinger CS, 1998, BIOORG MED CHEM LETT, V8, P3101

[9]

Garner P., 1991, ORG SYNTH, V70, P18

[10] New beta-hydroxyaspartate derivatives are competitive blockers for the bovine glutamate/aspartate transporter [J].

Lebrun, B ;

Sakaitani, M ;

Shimamoto, K ;

YasudaKamatani, Y ;

Nakajima, T .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (33) :20336-20339