Phosphonates as Modulators of Brain Chemistry

The present review describes the current knowledge on phosphonates designed for brain disease therapeutics, a less explored aspect of the studies on their medicinal chemistry. Because of their structural similarity with phosphates and of the ubiquitous presence of phosphate-dependent processes in the brain, phosphonate compounds are able to influence brain chemistry, interfering with neurotransmission and phosphorous-dependent bioprocesses. One of the main applications for phosphonates in the brain is Alzheimer's disease, for which they can be new drug candidates and/or afford innovative strategies for diagnostics. Such applications are described in the first section of this review, which includes a large number of reports on phosphonates with cholinesterase-inhibiting activity, some recent studies exploring phosphonates for inhibiting the interaction between amyloid-β protein and alcohol dehydrogenases, and phosphonate-based materials used in proteomics-based investigative and diagnosis platforms for the different stages of development of Alzheimer's disease. The second section of the review is dedicated to ischemic brain injury and to the development of phosphonates for active against NMDA and AMPA receptors with the purpose of reducing brain damage caused by glutamate excitotoxicity. Furthermore, agonists targeting the mGlu-4 receptor suggest potential for promoting neuroregeneration. The review concludes by emphasizing the relevance of phosphonate stability, versatility, and ability to mimic natural phosphate groups in the development of new therapeutic agents for brain disorders, weighing the advantages against the gaps in knowledge in order to set future directions of research in brain health.