The ultimate goal of this work is to commercialize a neuroimmunophilin ligand for cognition enhancement in patients with chronic neurodenerative disease. In preliminary studies in aged rats and primates, neuroimmunophilin ligands have been shown to enhance spatial learning and delayed matching-to-sample performance. However, the mechanism of action is not understood. In this Phase I feasibility study, we propose to elucidate the mechanism of action of the cognition enhancing effects of our neuroimmunophilin iigands. Understanding the mechanism will facilitate the design of more potent and selective compounds. Neuroimmunophilin ligands are orally active small molecules, which provide neuroprotection and stimulate morphologic and functional recovery of injured axons in multiple animal models of neurodegeneration. A prototype compound termed GPI 1485 is currently being evaluated in Phase II human clinical trials for Parkinson's Disease given at 1 gram 4 times per day. We propose to address the question of mechanism by identifying downstream binding targets of the GPI 1485-FKBP complex in neurons. We propose to use affinity chromatography and biochemical techniques to determine direct binding proteins of GPI 1485. We will complement these studies by evaluating mRNA and protein expression profiles in aged animals following cognition-enhancing drug treatment. In addition, the different biologic pathways utilized by FKBP ligands will be characterized. In future work following the successful completion of these proposed studies, we would then like to apply this mechanistic information towards re-designing, synthesizing and evaluating compounds with increased potency, more drug-like properties and better selectivity and specificity to treat cognitive deficits. ? ? ?
