Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists

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 IC 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 (3S,7aS)-7a-(4-chlorophenyl)-3-(4-hydroxybenzyl)tetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (compound 5 b) is a potential candidate for the treatment of pathologies associated with the over-activation of NMDA receptors.

Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca2+ Overload for the Treatment of Neurodegenerative Diseases and Stroke

“…The Ca 2+ entry was favored by addition of K + 70 mM to the extracellular medium. To evaluate the blocking effect of compounds on NMDA receptors, we have followed a protocol recently reported by our research group [ 45 ]. Rat cortical neurons were charged with Fluo-4/AM at 3 μM in Krebs-HEPES buffer and compounds incubated at same concentrations than before.…”

Title: A Boron‐Chelating Piperazine‐Tethered Schiff Base Can Modulate Excitability in Brain Slices in a Specific Frequency Range

“…[18] Although many NMDA channel blockers have been developed to date, moderate NMDA channel blockers are clinically preferred because they do not show serious side effects like high affinity channel blockers. [19] Ifenprodil is a drug that acts as an antagonist of the NMDA receptor, specifically targeting the GluN2B subunit of the receptor. [20] The GluN2B subunit is thought to be involved in the development of chronic pain and neurological disorders such as Alzheimer's disease.…”

Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders

“…Due to new information about the structural features of the NMDAR, [20][21][22][23][24][25] there was an increased interest on the development of new scaffolds targeting these receptors. In the last years we identified several aromatic amino alcohol-derived bicyclic lactams (compounds 4-5, Figure 2) [26][27][28][29] with antagonist properties of the NMDAR and activities in the same order of magnitude of memantine (2, Figure 1). developed by our research group.…”

“…developed by our research group. [26][27][28][29] Encouraged by our results, we decided to evaluate the impact of a more rigid scaffold on the modulation of the NMDAR activity as many known antagonists, acting on the ionic channel, have chemical structures with limited molecular mobility (e.g. MK-801 (1), memantine (2), amantadine (3), Figure 1).…”