Project Summary
The overall goal of this project is to identify a new drug lead that may be further developed to treat Alzheimer's disease (AD) through a mode of action that is different from currently available therapies.
Our first specific aim is to improve the drug-like properties of our current lead. We will use contemporary medicinal chemistry strategies to design and prepare new analogs that bind better and more selectively to a receptor (sigma receptor 2/progesterone receptor membrane component 1, or Sig2R/PGRMC1) that has only recently been associated with AD. The main thrust of this phase of our study is to identify a potential clinical candidate that can be orally dosed. We will first evaluate all new compounds in assays to determine their relative potencies and selectivities, and then we will assess the drug-like properties of the more promising candidates in a range of tests to assess their relative oral bioavailability.
Our second specific aim is to elucidate how compounds that bind to Sig2R/PGRMC1 affect neuron health and function. This important goal will be achieved using a series of electrophysiology and imaging techniques to study hippocampal neurons in vitro. These experiments will enable us to assess and understand how neuron firing, synapse plasticity, intracellular calcium ion levels, and morphology vary upon exposure to our compounds.
Our third specific aim is to assess how an optimized, orally-bioavailable drug candidate affects behavior and cognition in animal models. We will first perform a series of studies to determine oral bioavailability, brain exposure, and tolerance of several new compounds. We will then evaluate how the most promising clinical candidate affects performance of healthy and transgenic AD mice in a series of learning and memory tests. Plasma and tissue will then be analyzed for evidence of toxicity, and brain tissue will be studied for signs of reduced inflammation and neuroprotection.
The positive impacts arising from completion of our research are significant. We expect to identify an orally bioavailable lead to treat AD that can be advanced in studies that will enable filing of an Investigative New Drug Application with the FDA. Importantly, this new therapeutic approach has the potential to not only treat disease symptoms, but to slow disease progression. We anticipate that our neurophysiology studies will provide a better understanding of how Sig2R/PGRMC1 is involved in the health and function of neurons, and how modulating this receptor affects synapse integrity and communication between neurons. This knowledge will generally lead to a greater understanding of neurodegenerative processes and how these aberrant pathways might be suppressed.
