N-Methyl-d-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The over-activation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders.

Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by x-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC₅₀ values in a Ca²⁺ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.

ñ -甲基- ð天冬氨酸受体（NMDAR的）是中枢神经系统（CNS）的正常功能是至关重要的，并在存储器中的基本和学习有关的过程。这些受体的过度激活与许多神经退行性疾病和精神疾病有关。因此，NMDAR被认为是许多中枢神经系统疾病的相关治疗靶标。

在此，我们报道了一种具有拮抗NMDAR活性的新型支架的合成和药理学评价。具体而言，合成了十八种1-氨基茚满-2-醇四环内酰胺的化学文库，并将其筛选为NMDAR拮抗剂。通过使用对映体纯的1-氨基茚满-2-醇作为手性诱导剂，通过手性库合成获得了这些化合物，并通过X射线晶体学分析了两种目标化合物证明了它们的立体化学。大多数化合物显示NMDAR拮抗作用，而11种化合物在Ca ^2+中显示IC ₅₀值进入敏感的fluo-4分析方法，其剂量与临床批准的NMDAR拮抗剂美金刚相同。对接研究表明，由于与NMDAR通道共结晶的MK-801具有相容的构象，因此该新型化合物可以用作NMDAR通道阻滞剂。此外，我们表明四环1-氨基茚满-2-醇衍生物具有大脑渗透性，并且是无毒的，我们确定了有希望的命中点，可以进一步优化作为NMDAR功能的调节剂。