Neuroinflammation is a process in which brain cells not directly involved in carrying nerve impulses, called microglia, and inflammatory molecules, called cytokines, are elevated. This occurs even in normal aging brains, but is worse in Alzheimer's Disease (AD) and other neurodegenerative disorders. This is thought to underlie the symptoms of AD, including accumulation of amyloid-beta protein.Experience with chronic use of anti-inflammatory drugs in AD patients suggests that dampening inflammation can be of direct benefit to these patients. A major player in the activation of the glia is a cytokine, IL-1â, which is released by these cells early after activation and can also be taken up by other glia, to activate them in turn as well. The tight association between an ion channel, the P2X7 purinergic receptor, and the key intracellular apparatus responsible for processing and release of IL-1â by glia puts this molecular target at the very heart of neuroinflammation. Thus drugs which inhibit the activity of P2X7 will inhibit the release of IL-1â and therefore should be useful in treating brain inflammation. Decreasing brain inflammation can be expected to benefit AD and other neurodegenerative disease patients.The project aims at further developing a previously identified chemical class (ADDF Grant n. 20110203) which can yield, by means of a dedicated medicinal chemistry effort, potential new drugs that limit microglia over activation and neurotoxicity by specifically inhibiting the P2X7 receptor. Any potential drugs will be investigated for its biochemical activity and evaluated for its in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) profile, to lay the basis for subsequent pharmacological testing in an in vivo AD model, preclinical development, and clinical trials in the hope of introducing a new and effective means to treat AD.