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
收藏
页码：1681 / 1687
页数：7
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