Department of Medicinal Chemistry, Merck and Co., Inc., West Point, PA 19486, USA.
Curr Top Med Chem. 2010;10(2):170-86. doi: 10.2174/156802610790410974.
The simple amino acid glycine is implicated in both inhibitory and excitatory neurotransmission in mammalian central nervous system, and it modulates excitatory neurotransmission through its role as a necessary co-agonist for glutamatergic N-methyl-D-aspartate (NMDA) receptors. Given the involvement of NMDA receptor-mediated neurotransmission in complex cerebral processes such as cognition, pharmacological manipulation of extracellular synaptic glycine biology is an active area of pharmaceutical research to develop novel treatments for neuropsychiatric disorders. A key component of cerebral glycine metabolism is the glycine transporter type 1 (GlyT1) and elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to potentiate NMDA receptor function in vivo and to represent a rational approach for the treatment of schizophrenia and cognitive disorders. The present article will review the wealth of scientific evidence supporting that hypothesis and the medicinal chemistry effort by many pharmaceutical companies and academic institutions to develop potent and selective GlyT1 inhibitors.
简单的氨基酸甘氨酸参与了哺乳动物中枢神经系统中的抑制性和兴奋性神经递质传递，并且通过作为谷氨酸能 N-甲基-D-天冬氨酸 (NMDA) 受体的必需共激动剂的作用来调节兴奋性神经递质传递。鉴于 NMDA 受体介导的神经递质传递参与了认知等复杂的大脑过程，因此，对细胞外突触甘氨酸生物学的药理学操纵是开发新型神经精神疾病治疗方法的药物研究的一个活跃领域。大脑甘氨酸代谢的关键组成部分是甘氨酸转运蛋白 1（GlyT1），通过阻断 GlyT1 来提高细胞外突触甘氨酸浓度，据推测可以增强体内 NMDA 受体的功能，并代表治疗精神分裂症和认知障碍的合理方法。本文将综述大量科学证据支持这一假设，以及许多制药公司和学术机构为开发有效和选择性的 GlyT1 抑制剂所做的药物化学努力。
