Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

Xuechao Xing; Ling Chu Chang; Qiongman Kong; Craig K. Colton; Liching Lai; Marcie A. Glicksman; Chien Liang Glenn Lin; Gregory D. Cuny

doi:10.1016/j.bmcl.2011.08.009

Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

Xuechao Xing
, Ling Chu Chang
, Qiongman Kong
, Craig K. Colton
, Liching Lai
, Marcie A. Glicksman
, Chien Liang Glenn Lin
, Gregory D. Cuny

Neuroscience

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure-activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 μM after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5-3.9-fold after 24 h with an EC ₅₀ of 0.5 μM.

Original language	English
Pages (from-to)	5774-5777
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	19
DOIs	https://doi.org/10.1016/j.bmcl.2011.08.009
State	Published - Oct 1 2011

Keywords

Excitatory amino acid transporter 2
Excitotoxicity
Glutamate
Pyridazines

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@article{aa265238e406414ab21d78cca3126381,

title = "Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators",

abstract = "Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure-activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 μM after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5-3.9-fold after 24 h with an EC 50 of 0.5 μM.",

keywords = "Excitatory amino acid transporter 2, Excitotoxicity, Glutamate, Pyridazines",

author = "Xuechao Xing and Chang, \{Ling Chu\} and Qiongman Kong and Colton, \{Craig K.\} and Liching Lai and Glicksman, \{Marcie A.\} and Lin, \{Chien Liang Glenn\} and Cuny, \{Gregory D.\}",

note = "Funding Information: We are grateful to the National Institutes of Health ( U24 NS04933901 and R01 NS064275 ), the Harvard NeuroDiscovery Center, ALS Therapy Alliance, Inc and Project ALS for financial support. ",

year = "2011",

month = oct,

day = "1",

doi = "10.1016/j.bmcl.2011.08.009",

language = "English",

volume = "21",

pages = "5774--5777",

journal = "Bioorganic and Medicinal Chemistry Letters",

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TY - JOUR

T1 - Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

AU - Xing, Xuechao

AU - Chang, Ling Chu

AU - Kong, Qiongman

AU - Colton, Craig K.

AU - Lai, Liching

AU - Glicksman, Marcie A.

AU - Lin, Chien Liang Glenn

AU - Cuny, Gregory D.

N1 - Funding Information: We are grateful to the National Institutes of Health ( U24 NS04933901 and R01 NS064275 ), the Harvard NeuroDiscovery Center, ALS Therapy Alliance, Inc and Project ALS for financial support.

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure-activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 μM after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5-3.9-fold after 24 h with an EC 50 of 0.5 μM.

AB - Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure-activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations <5 μM after 24 h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5-3.9-fold after 24 h with an EC 50 of 0.5 μM.

KW - Excitatory amino acid transporter 2

KW - Excitotoxicity

KW - Glutamate

KW - Pyridazines

UR - https://www.scopus.com/pages/publications/80052599866

U2 - 10.1016/j.bmcl.2011.08.009

DO - 10.1016/j.bmcl.2011.08.009

M3 - Article

C2 - 21875806

AN - SCOPUS:80052599866

SN - 0960-894X

VL - 21

SP - 5774

EP - 5777

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 19

ER -

Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators

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Keywords

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