Camp Chad R, Banke Tue G, Xing Hao, Yu Kuai, Perszyk Riley E, Epplin Matthew P, Akins Nicholas S, Zhang Jing, Benke Tim A, Yuan Hongjie, Liotta Dennis C, Traynelis Stephen F
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
J Physiol. 2025 Jun 25. doi: 10.1113/JP288343.
N-Methyl-d-aspartate receptors (NMDARs) are a family of ligand-gated ionotropic glutamate receptors that mediate a slow, calcium-permeable component to excitatory neurotransmission. The GluN2D subunit is enriched in GABAergic inhibitory interneurons in cortical tissue. Diminished levels of GABAergic inhibition contribute to multiple neuropsychiatric conditions, suggesting that enhancing inhibition might have therapeutic utility, thus making GluN2D modulation an attractive drug target. Here, we describe the actions of a GluN2C/GluN2D-selective positive allosteric modulator, (+)-EU1180-453, which has improved drug-like properties, such as increased aqueous solubility, in comparison to the first-in-class GluN2C/GluN2D-selective prototypical positive allosteric modulator, (+)-CIQ. (+)-EU1180-453 doubles the NMDAR response at lower concentrations and produces a greater degree of maximal potentiation at 30 µM compared with (+)-CIQ. Using in vitro electrophysiological recordings, we show that (+)-EU1180-453 potentiates triheteromeric NMDARs containing at least one GluN2C or GluN2D subunit and is active at both exon5-lacking and exon5-containing GluN1 splice variants. (+)-EU1180-453 increases glutamate efficacy for GluN2C/GluN2D-containing NMDARs both by prolonging the deactivation time and by potentiating the peak response amplitude. We show that (+)-EU1180-453 selectively increases synaptic NMDAR-mediated charge transfer onto postnatal day 11-15 CA1 stratum radiatum hippocampal interneurons but is without effect on CA1 pyramidal cells. This increased charge transfer enhances inhibitory output from GABAergic interneurons onto CA1 pyramidal cells in a GluN2D-dependent manner. (+)-EU1180-453 also shifts excitatory-to-inhibitory coupling towards increased inhibition and produces enhanced gamma-band power from carbachol-induced field potential oscillations in hippocampal slices. Thus, (+)-EU1180-453 can enhance overall circuit inhibition, which could prove therapeutically useful for the treatment of anxiety, depression, schizophrenia and other neuropsychiatric disorders. KEY POINTS: (+)EU-1180-453 is a GluN2C/GluN2D positive allosteric modulator and is active at triheteromeric receptors. (+)EU-1180-453 is active at exon5-containing and exon5-lacking GluN1-containing receptors. (+)EU-1180-453 selectively potentiates the interneuron network and can enhance carbachol-induced gamma-band power.
N-甲基-D-天冬氨酸受体（NMDARs）是一类配体门控离子型谷氨酸受体，介导兴奋性神经传递中缓慢的、钙可通透的成分。GluN2D亚基在皮质组织的GABA能抑制性中间神经元中富集。GABA能抑制水平降低会导致多种神经精神疾病，这表明增强抑制作用可能具有治疗作用，因此使GluN2D调节成为一个有吸引力的药物靶点。在此，我们描述了一种GluN2C/GluN2D选择性正变构调节剂（+）-EU1180-453的作用，与第一代GluN2C/GluN2D选择性原型正变构调节剂（+）-CIQ相比，它具有改善的类药性质，如增加了水溶性。与（+）-CIQ相比，（+）-EU1180-453在较低浓度下使NMDAR反应加倍，并在30μM时产生更大程度的最大增强作用。利用体外电生理记录，我们表明（+）-EU1180-453增强了包含至少一个GluN2C或GluN2D亚基的三异聚体NMDARs的活性，并且对缺乏外显子5和含有外显子5的GluN1剪接变体均有活性。（+）-EU1180-453通过延长失活时间和增强峰值反应幅度，增加了含GluN2C/GluN2D的NMDARs的谷氨酸效力。我们表明，（+）-EU1180-453选择性地增加出生后第11至15天海马CA1辐射层中间神经元上突触NMDAR介导的电荷转移，但对CA1锥体细胞没有影响。这种增加的电荷转移以GluN2D依赖的方式增强了GABA能中间神经元对CA1锥体细胞的抑制输出。（+）-EU1180-453还将兴奋与抑制的耦合向增强抑制方向转变，并在海马切片中由卡巴胆碱诱导的场电位振荡中产生增强的γ波段功率。因此，（+）-EU1180-453可以增强整体电路抑制，这可能对治疗焦虑、抑郁、精神分裂症和其他神经精神疾病具有治疗作用。关键点：（+）EU-1180-453是一种GluN2C/GluN2D正变构调节剂，对三异聚体受体有活性。（+）EU-1180-453对含外显子5和不含外显子5的含GluN1受体有活性。（+）EU-1180-453选择性地增强中间神经元网络，并能增强卡巴胆碱诱导的γ波段功率。
