Discovery of functionally selective dopamine ligands for age-related cognitive decline

PROJECT SUMMARY/ABSTRACT Agonists for dopamine D1?like receptors (D1R) consistently have been shown to enhance cognitive functions (e.g., working memory) in normal, lesioned, and aged murine and primate species, including humans. The D1R also plays important roles in the regulation of synaptic plasticity and cognitive process that are damaged during age-related cognitive decline such as in Alzheimer?s disease (AD). Receptor functional selectivity/biased signaling is a useful approach for discovery of drugs with ability to activate differentially signaling pathways mediated by a single receptor. Our recent work suggested D1 functional selectivity has critical influence in modulation of working memory related behavior and neurophysiology in the prefrontal cortex of young adult rats. These and other data suggested functionally selective D1 ligands could be promising candidates for age-related cognitive decline. Here we propose a discovery project to understand how signaling bias affects the cognitive effects of D1 ligands, and to target novel functionally selective D1 agonists that may become potential IND candidates for the pharmacological treatment of age-related cognitive decline. This will be accomplished by the following three iterative but also independent specific aims, using recent advances in three field, in vitro pharmacology, in vivo behavioral and physiological neuroscience, and in silico ligand-target mechanistic studies. Aim 1 will examine behavioral and neurophysiological changes manifested by differential activation of D1 signaling pathways in aged versus young rats (24-month elderly and 5-month young adult Fisher, TgF344 transgenic AD rats). Pre-selected D1 ligands will be tested by a working memory related delayed alteration response task in the T-maze primarily, for their effects on behavior and neurophysiology. Aim 2 will use computational methods for ligand-target simulation to develop mechanism and accelerate drug discovery. Aim 3 will complete a thoroughly pharmacological screen to elucidate optimal D1 signaling profiles for age-related cognitive decline. This will involve characterization of receptor binding properties and functional assays, and off- target analysis, in not only heterologous expression systems but also brain tissue. The successful completion of proposed specific aims will provide heuristic information on the potential advantages of functionally selective D1 agonists for age-related cognitive decline. Recent clinical studies have shown, contrary to earlier views, that the D1R is a druggable target. Thus, this project will provide a rational foundation for selection of novel candidates for future IND-enabling studies and clinical trials.