拉帕替尼通过调节 N-甲基-D-天冬氨酸受体促进快速和持续的抗抑郁样作用。
Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects.
机构信息
Allergan, Plc, Irvine, California.
Allergan, Plc, Madison, New Jersey.
出版信息
Int J Neuropsychopharmacol. 2019 Mar 1;22(3):247-259. doi: 10.1093/ijnp/pyy101.
BACKGROUND
Modulation of glutamatergic synaptic transmission by N-methyl-D-aspartate receptors can produce rapid and sustained antidepressant effects. Rapastinel (GLYX-13), initially described as a N-methyl-D-aspartate receptor partial glycine site agonist, exhibits rapid antidepressant effect in rodents without the accompanying dissociative effects of N-methyl-D-aspartate receptor antagonists.
METHODS
The relationship between rapastinel's in vitro N-methyl-D-aspartate receptor pharmacology and antidepressant efficacy was determined by brain microdialysis and subsequent pharmacological characterization of therapeutic rapastinel concentrations in N-methyl-D-aspartate receptor-specific radioligand displacement, calcium mobilization, and medial prefrontal cortex electrophysiology assays.
RESULTS
Brain rapastinel concentrations of 30 to 100 nM were associated with its antidepressant-like efficacy and enhancement of N-methyl-D-aspartate receptor-dependent neuronal intracellular calcium mobilization. Modulation of N-methyl-D-aspartate receptors by rapastinel was independent of D-serine concentrations, and glycine site antagonists did not block rapastinel's effect. In rat medial prefrontal cortex slices, 100 nM rapastinel increased N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents and enhanced the magnitude of long-term potentiation without any effect on miniature EPSCs or paired-pulse facilitation responses, indicating postsynaptic action of rapastinel. A critical amino acid within the NR2 subunit was identified as necessary for rapastinel's modulatory effect.
CONCLUSION
Rapastinel brain concentrations associated with antidepressant-like activity directly enhance medial prefrontal cortex N-methyl-D-aspartate receptor activity and N-methyl-D-aspartate receptor-mediated synaptic plasticity in vitro. At therapeutic concentrations, rapastinel directly enhances N-methyl-D-aspartate receptor activity through a novel site independent of the glycine coagonist site. While both rapastinel and ketamine physically target N-methyl-D-aspartate receptors, the 2 molecules have opposing actions on N-methyl-D-aspartate receptors. Modest positive modulation of N-methyl-D-aspartate receptors by rapastinel represents a novel pharmacological approach to promote well-tolerated, rapid, and sustained improvements in mood disorders.
背景
N-甲基-D-天冬氨酸受体的谷氨酸能突触传递的调制可以产生快速和持续的抗抑郁作用。Rapastinel（GLYX-13）最初被描述为 N-甲基-D-天冬氨酸受体部分甘氨酸位点激动剂，在没有 N-甲基-D-天冬氨酸受体拮抗剂伴随的分离作用的情况下，在啮齿动物中显示出快速的抗抑郁作用。
方法
通过脑微透析和随后的 N-甲基-D-天冬氨酸受体特异性放射性配体置换、钙动员和内侧前额叶皮质电生理学测定，确定 Rapastinel 的体外 N-甲基-D-天冬氨酸受体药理学与抗抑郁疗效之间的关系。
结果
脑 Rapastinel 浓度为 30 至 100 nM 与抗抑郁样疗效相关，并增强 N-甲基-D-天冬氨酸受体依赖性神经元细胞内钙动员。Rapastinel 对 N-甲基-D-天冬氨酸受体的调制独立于 D-丝氨酸浓度，甘氨酸位点拮抗剂不阻断 Rapastinel 的作用。在大鼠内侧前额叶皮质切片中，100 nM Rapastinel 增加 N-甲基-D-天冬氨酸受体介导的兴奋性突触后电流，并增强长时程增强的幅度，而对微小 EPSC 或成对脉冲易化反应没有影响，表明 Rapastinel 的突触后作用。NR2 亚基内的一个关键氨基酸被确定为 Rapastinel 调节作用所必需。
结论
与抗抑郁样活性相关的 Rapastinel 脑浓度直接增强体外内侧前额叶皮质 N-甲基-D-天冬氨酸受体活性和 N-甲基-D-天冬氨酸受体介导的突触可塑性。在治疗浓度下，Rapastinel 通过一种新的、不依赖甘氨酸共激动剂位点的位点直接增强 N-甲基-D-天冬氨酸受体活性。虽然 Rapastinel 和氯胺酮都物理靶向 N-甲基-D-天冬氨酸受体，但这两种分子对 N-甲基-D-天冬氨酸受体的作用相反。Rapastinel 对 N-甲基-D-天冬氨酸受体的适度正调制代表了一种促进耐受性良好、快速和持续改善情绪障碍的新的药理学方法。
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