Memantine: A look ahead. Insights into structure, syntheses, receptor binding mechanisms, drug hybrids and formulations, and potential repurposing.

Since its approval for clinical use more than two decades ago, memantine has become a blockbuster drug against Alzheimer's disease (AD). Unlike other FDA approved small molecules for the treatment of AD, essentially acetyl cholinesterase inhibitors, memantine behaves as N-methyl-d-aspartate (NMDA) receptor antagonist. However, it is a weak and non-specific NMDA receptor channel blocker that has shown to be safe in slowing the decline of moderate to advanced AD symptoms. In fact, those of us familiarized with AD, are aware of clinical protocols where memantine is usually prescribed to mitigate late stages of this neurological disorder, following previous treatment with donepezil and other inhibitors. The role of memantine for either preventing or disrupting amyloid formation, yet promising, remains unconclusive. The pharmacological basis and mode of action of memantine are well known and have been reviewed from different standpoints, often within the context of adamantane scaffolds. In recent times, further analyses combining experiment and computational simulation have disclosed subtle features of memantine-receptor interactions and previously unrecognized mechanistic insights, which are summarized herein. Likewise, there is a growing interest in memantine derivatives, not only against neurodegeneration, but also versus unrelated pathologies. Such studies arising from lab observations and preclinical assessments at most, point to memantine's repurposing and open the door to further explorations and translation. It is noteworthy that some structural aspects of memantine, including crystal packing and polymorphism, are usually overlooked. This review pays attention to such key elements and updates synthetic protocols, including the first preparation of memantine in continuous flow.