N-hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor Ligands
N-hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor Ligands
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DOI：
10.1021/jm800025e
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发表时间：
2008-07-24
影响因子：
7.3
通讯作者：
Kristensen, Jesper L.
中科院分区：
文献类型：
--
作者：
Clausen, Rasmus P.;Christensen, Caspar;Kristensen, Jesper L.
本文设计、合成了一系列以N-羟基吡唑为生物电子等排体的天冬氨酸末端羧基类似物，并对其结构进行了表征。对主要谷氨酸受体亚组的亲和力研究表明，这些4-取代的N-羟基吡唑-5-基甘氨酸（NHP 5G）衍生物被N-甲基-D-天冬氨酸（NMDA）受体选择性识别，并且（R）对映体是优选的。此外，其中几种化合物能够区分NMDA受体中的各个亚型，提供了新的药理学工具。例如，4-丙基NHP 5G是NR 1/NR 2A亚型的拮抗剂，但却是NR 1/NR 2D亚型的激动剂。分子对接研究表明，取代基突出到一个区域，可以进一步利用，以提高亚型的选择性，从而开辟了配体，可以区分个别NMDA受体亚型的设计策略。
A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glycine (NHP5G) derivatives are selectively recognized by N-methyl-D-aspartic acid (NMDA) receptors and that the (R)enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For example, 4-propyl NHP5G is an antagonist at the NR1/NR2A subtype but an agonist at the NR1/NR2D subtype. Molecular docking studies indicate that the substituent protrudes into a region that may be further exploited to improve subtype selectivity, thereby opening up a design strategy for ligands which can differentiate individual NMDA receptor subtypes.