Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists. (22nd March 2017)

• Record Type: Journal Article
• Authors: Espadinha, Margarida; Dourado, Jorge; Lajarin‐Cuesta, Rocio; Herrera‐Arozamena, Clara; Gonçalves, Lidia M. D.; Rodríguez‐Franco, María Isabel; de los Rios, Cristobal; Santos, Maria M. M.
• Is Part Of: ChemMedChem. Volume 12:Number 7(2017)
• Page Start: 537
• Page End: 545
• Publication Date: 2017-03-22
• Subjects: antagonists -- asymmetric synthesis -- bicyclic lactams -- nitrogen heterocycles -- NMDA receptors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700037
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: N ‐Methyl‐d ‐aspartate (NMDA) receptors are fundamental for the normal function of the central nervous system (CNS), and play an important role in memory and learning. Over‐activation of these receptors leads to neuronal loss associated with major neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. In this study, 22 novel enantiopure bicyclic lactams were designed, synthesized, and evaluated as NMDA receptor antagonists. Most of the new compounds displayed NMDA receptor antagonism, and the most promising compound showed an IC50 value on the same order of magnitude as that of memantine, an NMDA receptor antagonist in clinical use for the treatment of Alzheimer's disease. Further biological evaluation indicated that this compound is brain permeable (determined by an in vitro assay) and non‐hepatotoxic. All these results indicate that (3 S, 7a S )‐7a‐(4‐chlorophenyl)‐3‐(4‐hydroxybenzyl)tetrahydropyrrolo[2, 1‐ b ]oxazol‐5(6 H )‐one (compound5 b ) is a potential candidate for the treatment of pathologies associated with the over‐activation of NMDA receptors. Abstract : Catch 22 : Twenty two novel enantiopure bicyclic lactams were synthesized and evaluated as NMDA receptor antagonists. The most promising compound displayed an IC50 value on the same order of magnitude as that of memantine. In vitro assays indicated that this compound is brain permeable and non‐hepatotoxic; it is a potential candidate for the treatment of pathologies associated with the over‐activation of NMDA receptors.