Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Curr Top Med Chem. 2011;11(7):887-906. doi: 10.2174/156802611795164990.
The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally α-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist binding pocket is filled, but also how it affects the conformational space of the ligand and in this way restricts the recognition of various glutamate receptors, ultimately leading to selectivity.
神经递质 (S)-谷氨酸 [(S)-Glu] 负责中枢神经系统中大多数兴奋性神经递质的传递。(S)-Glu 的作用是通过离子型和代谢型受体介导的。谷氨酸受体激动剂通常是具有一个或多个手性中心的α-氨基酸，这是由于受体激活状态的激动剂结合口袋中存在严格的要求。相比之下，有许多非手性竞争性拮抗剂的例子。本综述探讨了立体化学如何影响谷氨酸受体配体的活性。该综述主要关注激动剂，并讨论了立体化学和构象考虑因素以及激动剂结合口袋的生物结构知识，这对于设计谷氨酸受体激动剂很有用。选择的例子表明立体化学不仅决定了激动剂结合口袋如何被填充，还决定了它如何影响配体的构象空间，并以这种方式限制了对各种谷氨酸受体的识别，最终导致选择性。
