Marchesani Francesco, Rebecchi Francesca, Pieroni Marco, Faggiano Serena, Annunziato Giannamaria, Spaggiari Chiara, Bruno Stefano, Rinaldi Sofia, Giaccari Roberta, Costantino Gabriele, Campanini Barbara
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
Department of Food and Drug, University of Parma, 43124 Parma, Italy.
ACS Med Chem Lett. 2024 Jul 3;15(8):1298-1305. doi: 10.1021/acsmedchemlett.4c00174. eCollection 2024 Aug 8.
The intricate signaling network within the central nervous system (CNS) involving -methyl-d-aspartate receptors (NMDARs) has been recognized as a key player in severe neurodegenerative diseases. The indirect modulation of NMDAR-mediated neurotransmission through inhibition of serine racemase (SR)-the enzyme responsible for the synthesis of the NMDAR coagonist d-serine-has been suggested as a therapeutic strategy to treat these conditions. Despite the inherent challenges posed by SR conformational flexibility, a ligand-based drug design strategy has successfully produced a series of potent covalent inhibitors structurally related to amino acid analogues. Among these inhibitors, O-(2-([1,1'-biphenyl]-4-yl)-1-carboxyethyl)hydroxylammonium chloride () has emerged as a valuable candidate with a of about 5 μM, which makes it one of the most potent hSR inhibitors reported to date. This molecule is expected to inspire the identification of selective hSR inhibitors that might find applications as tools in the study and treatment of several CNS pathologies.
中枢神经系统（CNS）内涉及N-甲基-D-天冬氨酸受体（NMDARs）的复杂信号网络已被认为是严重神经退行性疾病的关键因素。通过抑制丝氨酸消旋酶（SR）（负责合成NMDAR共激动剂D-丝氨酸的酶）来间接调节NMDAR介导的神经传递，已被提议作为治疗这些疾病的一种策略。尽管SR构象灵活性带来了内在挑战，但基于配体的药物设计策略已成功产生了一系列与氨基酸类似物结构相关的强效共价抑制剂。在这些抑制剂中，O-(2-([1,1'-联苯]-4-基)-1-羧乙基)羟氯化铵（）已成为一种有价值的候选物，其IC50约为5μM，这使其成为迄今为止报道的最有效的人SR抑制剂之一。预计该分子将激发选择性人SR抑制剂的鉴定，这些抑制剂可能作为工具应用于几种中枢神经系统疾病的研究和治疗。
