Terry-Lorenzo Ryan T, Fan Reuben H, Khin Ni A, Singh Jaskaran B
Neurocrine Biosciences, Inc., San Diego, CA, United States.
Int J Neuropsychopharmacol. 2024 Dec 28;28(1). doi: 10.1093/ijnp/pyae066.
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been proposed to underlie the pathophysiology of schizophrenia, suggesting that promoting NMDAR activity may alleviate the negative or cognitive symptoms associated with schizophrenia. To circumvent excitotoxicity that may accompany direct agonism of the glutamate binding site on the NMDAR, therapeutic trials have focused on targeting the glycine binding site on the NMDAR. Direct administration of either glycine or D-serine, both of which are endogenous coagonists at the NMDAR glycine site, has yielded mixed outcomes across an array of clinical trials investigating different doses or patient populations. Furthermore, directly administering D-serine and glycine is challenging, and thus attention has turned to alternative, indirect methods that increase endogenous D-serine and glycine levels in the brain, such as D-amino acid oxidase (DAAO) inhibitors and glycine transporter 1 inhibitors, respectively. In this review, we provide an overview of the evidence supporting the potential of NMDAR modulators in general, and DAAO inhibitors in particular, as potential adjunctive treatments for schizophrenia. We also discuss the preclinical and clinical data related to luvadaxistat, an investigational highly selective and potent DAAO inhibitor that was under development for the treatment of the cognitive impairment associated with schizophrenia.
N-甲基-D-天冬氨酸受体（NMDAR）功能减退被认为是精神分裂症病理生理学的基础，这表明增强NMDAR活性可能会缓解与精神分裂症相关的阴性或认知症状。为了规避因直接激动NMDAR上的谷氨酸结合位点可能伴随的兴奋性毒性，治疗试验聚焦于靶向NMDAR上的甘氨酸结合位点。直接给予甘氨酸或D-丝氨酸（二者均为NMDAR甘氨酸位点的内源性共激动剂），在一系列针对不同剂量或患者群体的临床试验中产生了喜忧参半的结果。此外，直接给予D-丝氨酸和甘氨酸具有挑战性，因此人们将注意力转向了替代的间接方法，即分别提高大脑中内源性D-丝氨酸和甘氨酸水平的方法，如D-氨基酸氧化酶（DAAO）抑制剂和甘氨酸转运体1抑制剂。在本综述中，我们概述了支持NMDAR调节剂，特别是DAAO抑制剂作为精神分裂症潜在辅助治疗药物的证据。我们还讨论了与鲁伐达西他相关的临床前和临床数据，鲁伐达西他是一种正在研发的用于治疗与精神分裂症相关认知障碍的高选择性强效DAAO抑制剂。
