Diamonds for the Mind: Exploring the Potential of Adamantane against Alzheimer's Disease

Alzheimer's disease (AD) is the predominant type of dementia, emerging as a major health issue globally due to its increasing incidence and the limited approved therapies that provide only symptomatic relief. Adamantane, a diamondoid hydrocarbon with a distinctive cage-like structure, has emerged as a promising scaffold in medicinal chemistry due to its high lipophilicity, leading to good central nervous system bioavailability. Notably, memantine, an NMDA (N-methyl-daspartate) receptor antagonist, is an adamantane derivative that is approved by the U.S. Food and Drug Administration (US FDA) to manage moderate-to-severe AD symptoms. This review analyses the structure-activity relationship (SAR) of several adamantane derivatives and their relevance to AD. Amino-substituted adamantanes, such as amantadine and memantine, display anti-Alzheimer potential due to improved NMDA receptor affinity and CNS permeability. Additional targets, such as voltage-gated sodium channels and retinoid receptors, are proposed as potential targets for adamantane derivatives developed to act against AD. While various adamantane compounds have been patented and studied, few have become clinically approved drugs. Structural changes, particularly at bridgehead carbon atoms, greatly influence pharmaceutical results. Adamantane's physicochemical features make it a preferred framework for future CNS-targeted therapies. Given the increasing need for more effective AD treatments, adamantane-based compounds present a viable option for new drug development.