Abstract
Multi-target-directed ligands (MTDLs) offer new hope for the treatment of multifactorial complex diseases such as Alzheimer’s Disease (AD). Herein, we present compounds aimed at targeting the NMDA and the P2X7 receptors, which embody a different approach to AD therapy. On one hand, we are seeking to delay neurodegeneration targeting the glutamatergic NMDA receptors; on the other hand, we also aim to reduce neuroinflammation, targeting P2X7 receptors. Although the NMDA receptor is a widely recognized therapeutic target in treating AD, the P2X7 receptor remains largely unexplored for this purpose; therefore, the dual inhibitor presented herein—which is open to further optimization—represents the first member of a new class of MTDLs.
Highlights
Alzheimer’s disease (AD) is an afflicting neurodegenerative disorder that triggers a progressive loss of neurons and synapses, leading to an irreversible cognitive decline and eventually to death [1,2,3]
We envisaged the aminoadamantylcarbohydrazides of general structure I as putative dual inhibitors (Figure 1)
N-methyl-D-aspartate receptor (NMDAR) antagonist (IC50 = 92 ± 29 μM) [42]; secondly, the N’-arylcarbohydrazide moiety of 1a is a compound endowed with nanomolar P2X7 receptors (P2X7R) antagonist activity (IC50 = 11.6 ± 2 nM) [43]
Summary
Alzheimer’s disease (AD) is an afflicting neurodegenerative disorder that triggers a progressive loss of neurons and synapses, leading to an irreversible cognitive decline and eventually to death [1,2,3]. The pathophysiology of AD is still not completely understood, it is widely accepted that the accumulation of extracellular plaques is one of the major hallmarks in AD [14,15,16,17,18,19]. These plaques are mainly composed of beta-amyloid peptide and activated microglia; in the first instance, they produce a neuroprotective inflammatory response to repair damage [20,21]. Its physiological activation in other CNS cell lines—as granular neurons—links to calcium-dependent neuroprotective events such as cAMP response element-binding (CREB) activation [26]; this is responsible for protection against glutamate-induced
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