DESCRIPTION (provided by applicant): An unfortunate result of the rapid rise in the geriatric population in developed countries is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that inflicts an enormous emotional and financial toll on patients as well as caregivers. Unfortunately, the currently available therapies for AD are limited by modest efficacy, adverse side effects, and the fact that the very problematic non-cognitive behavioral symptoms (e.g., agitation) of the illness are left untreated. Such behavioral symptoms are thus;often managed clinically by potent antipsychotic drugs, compounds that are known to produce a variety of adverse metabolic and cardiovascular reactions which are particularly problematic in older patients. Accordingly, one long-term goal of our laboratory is to develop more safe and effective therapeutic agents for patients suffering from both the behavioral and cognitive symptoms of dementia. We have identified one especially promising compound in our drug discovery program that has potential to address these challenges. The compound, JWS-USC-75-IX, is a ranitidine analog that has potent acetylcholinesterase inhibitor (AChEI) properties (i.e., an important therapeutic target for memory enhancement) as well as antagonist activity at both muscarinic (M2) acetylcholine and histamine (H3) receptors (i.e., important drug targets for both cognitive enhancement and antipsychotic activity). Thus, the objective of this application is to determine in animal models if JWS-USC-75-IX is a viable prototypical AD therapeutic agent as well as to provide a proof of concept for the usefulness of single molecular entities with multiple therapeutic targets. Our central hypothesis is that as a result of its activity at multiple drug targets, JWS-USC 75-IX will demonstrate cognitive enhancing effects as well as antipsychotic activity in experimental animal models. To achieve the objectives of this application, we propose two specific aims: 1) To determine the procognitive potential of JWS-USC-75-IX in the aged non-human primate;and 2) To determine the antipsychotic potential of JWS-USC-75-IX in rodents. To address these aims, we will evaluate JWS-USC-75-IX in a delayed match to sample (DMTS) task and a distractor version of this method (DMTS-D) in aged monkeys for effects on working memory and attention, respectively. We will determine antipsychotic potential of the compound in rodents in an amphetamine-induced locomotor activity model and a prepulse inhibition procedure. The significance of this project and its relevance to public health is exemplified by the potential of this novel compound to address two major therapeutic challenges (i.e., cognitive deficits and non-cognitive behavioral symptoms) that are associated not only with neurological illnesses such as AD, but also in psychiatric illnesses such as schizophrenia (i.e., conditions that affect millions of people worldwide). PUBLIC HEALTH RELEVANCE Cognitive deficits and non-cognitive behavioral symptoms are two major therapeutic challenges associated with Alzheimer's disease (AD) and psychiatric illnesses such as schizophrenia. We have synthesized a particularly promising compound (the ranitidine analog, JWS-USC-75-IX) that has potent activity in vitro at three important molecular targets for procognitive and antipsychotic activity, thus potentially addressing these therapeutic challenges in a single molecule. The experiments proposed in this application will thus determine (in animal behavior models) the viability of JWS-USC-75-IX as a prototypical AD-therapeutic agent, and will provide a proof of concept for the usefulness of single molecular entities with multiple therapeutic targets.
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