Tzschentke T M
Grünenthal GmbH, Research and Development, Department of Pharmacology, Aachen, Germany.
Amino Acids. 2002;23(1-3):147-52. doi: 10.1007/s00726-001-0120-8.
Glutamate is the most widely distributed excitatory transmitter in the central nervous system (CNS). It is acting via large - and still growing - families of receptors: NMDA-, AMPA-, kainate-, and metabotropic receptors. Glutamate has been implicated in a large number of CNS disorders, and it is hoped that novel glutamate receptor ligands offer new therapeutic possibilities in disease states such as chronic pain, stroke, epilepsy, depression, drug addiction and dependence or Parkinson's disease. While an extensive preclinical literature exists showing potential beneficial effects of NMDA-, AMPA-, kainate- and metabotropic receptor ligands, only NMDA receptor antagonists have been characterized clinically to any appreciable degree. In these trials it has been shown that while several compounds are therapeutically active, they also produce serious side effects at therapeutic doses. Current interest largely centers on the development of receptor subtype-selective compounds, namely compounds selective for receptors containing the NR2B subunit. Preclinical findings and the first clinical results are encouraging, and it may be that such subunit-selective compounds may have a sufficiently wide therapeutic window to be safe for human use.
谷氨酸是中枢神经系统（CNS）中分布最广泛的兴奋性神经递质。它通过大量且仍在不断增加的受体家族发挥作用：N-甲基-D-天冬氨酸（NMDA）受体、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体、海人藻酸（kainate）受体和代谢型受体。谷氨酸与大量中枢神经系统疾病有关，人们希望新型谷氨酸受体配体能为慢性疼痛、中风、癫痫、抑郁症、药物成瘾和依赖或帕金森病等疾病状态提供新的治疗可能性。虽然存在大量临床前文献表明NMDA受体、AMPA受体、海人藻酸受体和代谢型受体配体具有潜在的有益作用，但只有NMDA受体拮抗剂在临床上得到了一定程度的表征。在这些试验中已经表明，虽然几种化合物具有治疗活性，但它们在治疗剂量下也会产生严重的副作用。目前的研究兴趣主要集中在受体亚型选择性化合物的开发上，即对含有NR2B亚基的受体具有选择性的化合物。临床前研究结果和首批临床结果令人鼓舞，也许这种亚基选择性化合物可能具有足够宽的治疗窗，对人类使用是安全的。
