Direct and Indirect Modulation of the N-Methyl D-Aspartate Receptor: Potential for the Development of Novel Antipsychotic Therapies
Direct and Indirect Modulation of the N-Methyl D-Aspartate Receptor: Potential for the Development of Novel Antipsychotic Therapies
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DOI：
10.2174/1568007023339544
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Conn, P. Jeffrey
中科院分区：
文献类型：
--
作者：
Marino, M. J.;Conn, P. Jeffrey
精神分裂症的多巴胺假说一直是指导精神分裂症病理生理学理论和该领域药物发现工作的驱动力。虽然这条道路在更深入地了解这种疾病和各种抗精神病药物方面取得了丰硕的成果，但人们普遍认识到，靶向D-2多巴胺受体存在多个缺点。最近，已提出在多巴胺能系统的改变发挥关键作用的神经化学破坏精神分裂症的基础。特别是，精神分裂症的症状和非竞争性N-甲基D-天冬氨酸（NMDA）受体拮抗剂，如苯环利定的拟精神病的影响之间的相似性，激发了兴趣的可能性，NMDA受体功能减退状态可能是精神分裂症的基础。本文综述了精神分裂症的NMDA功能低下假说，并重点介绍了NMDA受体作为新型抗精神病药物的潜在靶点。NMDA受体上的调节位点以及G蛋白偶联受体如调节NMDA受体的毒蕈碱和代谢型谷氨酸受体都是开发可改善精神分裂症症状的新型化合物的潜在靶点。
The dopamine hypothesis of schizophrenia has been a driving force in guiding both theories of pathophysiology of schizophrenia, and drug discovery efforts in this area. While this path has been fruitful in producing a deeper understanding of the disorder and a variety of antipsychotic drugs, it is generally recognized that targeting the D-2 dopamine receptor has multiple shortcomings. Recently, alterations in the glutamatergic system have been proposed to play a key role in the neurochemical disruptions underlying schizophrenia. In particular, the similarities between the symptoms of schizophrenia and the psychotomimetic effects of non-competitive N-methyl D-aspartate (NMDA) receptor antagonists such as phencyclidine have spurred interest in the possibility that an NMDA receptor hypofunctional state might underlie schizophrenia. In this review, we summarize the NMDA hypofunction hypothesis of schizophrenia, and focus on the NMDA receptor as a potential target for novel antipsychotic agents. Both modulatory sites on the NMDA receptor, as well as G-protein coupled receptors such as the muscarinic and metabotropic glutamate receptors that modulate the NMDA receptor, are potential targets for the development of novel compounds that could ameliorate the symptoms of schizophrenia.