Chazot Paul L
Sunderland Pharmacy School, University of Sunderland, Sunderland, Tyne and Wear SR2 3SD, UK.
Curr Med Chem. 2004 Feb;11(3):389-96. doi: 10.2174/0929867043456061.
The NMDAR2B subunit is the focus of increasing interest as a therapeutic target in a wide range of CNS pathologies, including acute and chronic pain, stroke and head trauma, drug-induced dyskinesias, and dementias. Due to significant pharmaceutical endeavor, an impressive collection of chemical leads has been developed which target the NR2B subunit, some of which appear to discriminate between closely related subtypes. We now have the benefit of a structural template for the ifenprodil binding site which should further improve future structure activity relationships. A growing appreciation of the likely extrasynaptic localisation of the NR2B receptor subtype and importance of NR2B protein modification, notably tyrosine phosphorylation, may explain its therapeutic importance. The apparent superior preclinical and clinical data for the second and third generation NR2B compounds is likely to reflect subtype selectivity, a unique mode of action and cellular location of the NR2B receptors in the CNS.
NMDAR2B亚基作为治疗靶点在多种中枢神经系统疾病中越来越受到关注，这些疾病包括急慢性疼痛、中风和头部创伤、药物性运动障碍以及痴呆症。由于大量的药物研发工作，已经开发出了一系列针对NR2B亚基的化学先导物，其中一些似乎能够区分密切相关的亚型。现在我们有了艾芬地尔结合位点的结构模板，这将进一步改善未来的构效关系。对NR2B受体亚型可能存在的突触外定位以及NR2B蛋白修饰（尤其是酪氨酸磷酸化）重要性的认识不断提高，这可能解释了其治疗重要性。第二代和第三代NR2B化合物明显更好的临床前和临床数据可能反映了亚型选择性、独特的作用模式以及NR2B受体在中枢神经系统中的细胞定位。
