Lindsley Craig W, Wolkenberg Scott E, Kinney Gene G
Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Curr Top Med Chem. 2006;6(17):1883-96. doi: 10.2174/156802606778249784.
Clinically utilized antipsychotic agents share as a common mechanism the ability to antagonize dopamine D2 receptors and it is widely assumed that this activity contributes to their efficacy against the positive symptoms of schizophrenia. The efficacy of currently marketed antipsychotic agents on the negative and cognitive symptoms of this disease, however, is not optimal. One alternate hypothesis to the "dopamine hypothesis" of schizophrenia derives from the observation that antagonists of NMDA receptor activity better mimic the symptomatology of schizophrenia in its entirety than do dopamine agonists. Findings from this line of research have led to the NMDA receptor hypofunction (or glutamate dysfunction) hypothesis of schizophrenia, which complements existing research implicating dopamine dysfunction in the disease. According to the NMDA receptor hypofunction hypothesis, any treatment that enhances NMDA receptor activity may prove useful for the treatment of the complex symptoms that define schizophrenia. This idea is now supported by numerous clinical studies that have reported an efficacious response following treatment with activators of the NMDA receptor co-agonist glycineB site. One area of study, aimed at potentiating the NMDA receptor via activation of the glycineB site is small molecule blockade of the glycine reuptake transporter type 1 (GlyT1). Broadly, these efforts have focused on derivatives of the substrate inhibitor, sarcosine, and non-sarcosine based GlyT1 inhibitors. Accordingly, the following review discusses the development of both sarcosine and non-sarcosine based GlyT1 inhibitors and their current status as putative treatments for schizophrenia and other disorders associated with NMDA receptor hypoactivity.
临床上使用的抗精神病药物具有一个共同机制，即能够拮抗多巴胺D2受体，人们普遍认为这种活性有助于其对抗精神分裂症的阳性症状。然而，目前市面上的抗精神病药物对该疾病的阴性和认知症状的疗效并不理想。精神分裂症“多巴胺假说”的一个替代假说是基于这样的观察：NMDA受体活性拮抗剂比多巴胺激动剂更能全面地模拟精神分裂症的症状。这一系列研究结果导致了精神分裂症的NMDA受体功能减退（或谷氨酸功能障碍）假说，该假说补充了现有的关于多巴胺功能障碍与该疾病相关的研究。根据NMDA受体功能减退假说，任何增强NMDA受体活性的治疗方法可能对治疗精神分裂症的复杂症状有用。这一观点现在得到了众多临床研究的支持，这些研究报告称，用NMDA受体共激动剂甘氨酸B位点的激活剂治疗后有有效的反应。一个旨在通过激活甘氨酸B位点增强NMDA受体的研究领域是对1型甘氨酸再摄取转运体（GlyT1）的小分子阻断。广泛地说，这些努力集中在底物抑制剂肌氨酸的衍生物以及非肌氨酸基的GlyT1抑制剂上。因此，以下综述讨论了肌氨酸和非肌氨酸基GlyT1抑制剂的开发及其作为精神分裂症和其他与NMDA受体活性减退相关疾病的潜在治疗方法的现状。
