Nγ-Aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site

被引：132

作者：

Esslinger, CS ^{[1
]}

Cybulski, KA ^{[1
]}

Rhoderick, JF ^{[1
]}

机构：

[1] Univ Montana, NIH, COBRE, Ctr Ctruct & FUnct Neurosci,Dept Biomed & Pharmac, Missoula, MT 59812 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 04期

关键词：

pharmacophore; modeling; inhibition; H-bonding;

D O I：

10.1016/j.bmc.2004.11.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Analogues of L-glutamine were designed and synthesized to test a hydrogen-bond hypothesis between ligand and neutral amino acid transporter ASCT2. The key design feature contains a substituted phenyl ring on the amide nitrogen that contains electron withdrawing and electron donating groups that alter the pK(a) of the amide NH. Through this study a preliminary binding site map has been developed, and a potent commercially available competitive inhibitor of the ASCT2 transporter has been identified. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：1111 / 1118

页数：8

共 31 条

[21]

LEVINTOW L, 1954, J BIOL CHEM, V209, P265

[22]

Li RL, 2003, ANTICANCER RES, V23, P3413

[23] Nonlinear free energy relationship in the general-acid-catalyzed acylation of rat kidney γ-glutamyl transpeptidase by a series of γ-glutamyl anilide substrate analogues [J].

Ménard, A ;

Castonguay, R ;

Lherbet, C ;

Rivard, C ;

Roupioz, Y ;

Keillor, JW .

BIOCHEMISTRY, 2001, 40 (42) :12678-12685

[24]

PARKER CM, 1990, Patent No. 9003399

[25] Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools:: further evidence for metabolic compartmentation [J].

Rae, C ;

Hare, N ;

Bubb, WA ;

McEwan, SR ;

Bröer, A ;

McQuillan, JA ;

Balcar, VJ ;

Conigrave, AD ;

Bröer, S .

JOURNAL OF NEUROCHEMISTRY, 2003, 85 (02) :503-514

[26]

RENNIE MJ, 1986, LANCET, V2, P1008

[27] Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter [J].

UtsunomiyaTate, N ;

Endou, H ;

Kanai, Y .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (25) :14883-14890

[28] Cloning and functional identification of a neuronal glutamine transporter [J].

Varoqui, H ;

Zhu, HM ;

Yao, DD ;

Ming, H ;

Erickson, JD .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (06) :4049-4054

[29] Characterization of L-glutamine transport by a human neuroblastoma cell line [J].

Wasa, M ;

Wang, HS ;

Okada, A .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2002, 282 (06) :C1246-C1253

[30] ASCT-1 is a neutral amino acid exchanger with chloride channel activity [J].

Zerangue, N ;

Kavanaugh, MP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (45) :27991-27994

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