Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

被引：21

作者：

Maolanon, Alex R. ^{[1
]}

Risgaard, Rune ^{[1
]}

Wang, Shuang-Yan ^{[1
]}

Snoep, Yoran ^{[1
]}

Papangelis, Athanasios ^{[1
]}

Yi, Feng ^{[2
,3
]}

Holley, David ^{[2
,3
]}

Barslund, Anne F. ^{[1
,4
]}

Svenstrup, Niels ^{[4
]}

Hansen, Kasper B. ^{[2
,3
]}

Clausen, Rasmus P. ^{[1
]}

机构：

[1] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark

[2] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA

[3] Univ Montana, Ctr Biomol Struct & Dynam, Missoula, MT 59812 USA

[4] H Lundbeck & Co AS, Neurosci Drug Discovery, Ottiliavej 9, DK-2500 Valby, Denmark

来源：

ACS CHEMICAL NEUROSCIENCE | 2017年 / 8卷 / 08期

关键词：

lonotropic glutamate receptor; NMDA; superagonist; D-serine; D-cycloserine; subtype selectivity; POSITIVE ALLOSTERIC MODULATORS; D-ASPARTATE RECEPTOR; D-CYCLOSERINE; STRUCTURAL DETERMINANTS; GLUTAMATE; SUBUNIT; EXTINCTION; MECHANISM; EFFICACY; DESIGN;

D O I：

10.1021/acschemneuro.7b00117

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：

A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

引用

页码：1681 / 1687

页数：7

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