Mechanism of Inhibition of Viral and Neuronal Pore Loop Ion Channels by the Adamantanes

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Essentially all living cells have channel-like proteins embedded in their cell walls. The presence of these channels selectively allow certain classes of charged molecules, or ions, to pass into or out of the cellular interiors, as cell walls by themselves are normally impermeable to such molecules. Channels are often critical components of cells, and opening and closing ion channels is at the centre of many normal cellular processes such as cell fate decisions or intercellular communication. Ion channels are also at the root of some abnormal processes that arise from genetic mutations such as multiple sclerosis, or have functions that are essential for pathogen viability such as in the influenza virus. For this reason, many useful drugs act by forcing ion channels to open or close. One family of drugs that function in this way are the adamantanes. They bind to, and close, a surprisingly wide variety of ion channels, including a proton channel in the flu virus called M2, and calcium channels that are found in humans at neuronal synapses called NMDA receptors, which are involved in memory and learning. For these reasons, adamantanes are prescribed both for the treatment of flu infections, and to alleviate the symptoms of neurodegeneration associated with diseases such as Parkinsons and Alzheimers. Drugs typically interact specifically with proteins such as ion channels at one particular site, and knowing the precise physical properties of those interactions can facilitate design of more specific, and therefore more effective or less toxic drugs. In previous work, we elucidated the physical location at which the adamantanes bind to the flu virus ion channel. Unfortunately, little is known about the same process in the NMDA receptor. We now hope to use what we learned in the M2 case, to understand what physical interactions are needed for binding to the NMDA receptors. In addition, adamantanes such as amantadine and memantine are part of a larger class of potentially therapeutic compounds that bind to the NMDA receptor. Thus, understanding the behaviour of the adamantanes may be broadly applicable for guiding development of more effective drug treatments for neurodegenerative diseases.