Zhao Fabao, Atxabal Unai, Mariottini Sofia, Yi Feng, Lotti James S, Layeux Michael S, Currier Chandler, Maderia Matthew P, Cornelison Lauren E, Anderson Carly M, Schultz Eric P, Zhang Zhucheng, Jiang Liyang, Gao Zhen, Liu Na, Woodahl Erica L, Bunch Lennart, Hansen Kasper B, Clausen Rasmus P
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 250012 Jinan, Shandong P. R. China.
J Med Chem. 2025 Feb 13;68(3):3572-3590. doi: 10.1021/acs.jmedchem.4c02715. Epub 2025 Jan 23.
NMDA receptor ligands have therapeutic potential in neurological and psychiatric disorders. We designed ()-3-(5-thienyl)carboxamido-2-aminopropanoic acid derivatives with nanomolar agonist potencies at NMDA receptor subtypes (GluN12/A-D). These compounds are superagonists at GluN1/2C compared to glycine and partial to full agonists at GluN1/2A and GluN1/2D but display functional antagonism at GluN1/2B due to low agonist efficacy. Notably, display 864% agonist efficacy at GluN1/2C relative to glycine, and has high potency at GluN1/2A (0.018 μM), GluN1/2C (0.0029 μM), and GluN1/2D (0.016 μM). We evaluated the binding mode in the glycine site using molecular modeling and mutagenesis. absorption, distribution, metabolism, and excretion (ADME) assays predict high metabolic stability but poor blood-brain barrier permeability. However, an ester prodrug for the carboxylate group of display moderately high blood-brain barrier permeability. The thiophenecarboxamide agonists expand the synthetic pharmacology of NMDA receptors and provide structural insights that facilitate the design of GluN1 agonists with GluN2 subunit-specific activity.
NMDA受体配体在神经和精神疾病中具有治疗潜力。我们设计了在NMDA受体亚型（GluN1-2A-D）上具有纳摩尔激动剂效力的()-3-(5-噻吩基)羧酰胺-2-氨基丙酸衍生物。与甘氨酸相比，这些化合物在GluN1/2C上是超激动剂，在GluN1/2A和GluN1/2D上是部分至完全激动剂，但由于激动剂效力低，在GluN1/2B上表现出功能性拮抗作用。值得注意的是，相对于甘氨酸，在GluN1/2C上显示出864%的激动剂效力，并且在GluN1/2A（0.018μM）、GluN1/2C（0.0029μM）和GluN1/2D（0.016μM）上具有高效力。我们使用分子建模和诱变评估了甘氨酸位点的结合模式。吸收、分布、代谢和排泄（ADME）分析预测其具有高代谢稳定性，但血脑屏障通透性较差。然而，的羧酸盐基团的酯前药显示出中等程度的高血脑屏障通透性。噻吩甲酰胺激动剂扩展了NMDA受体的合成药理学，并提供了有助于设计具有GluN2亚基特异性活性的GluN1激动剂的结构见解。
