Novel Alpha1A-Adrenergic Receptor Agonists to Treat Alzheimer's Disease

We need to develop new drugs to treat Alzheimer’s disease (AD), ones that work in different ways than current treatments, because current drugs and clinical trials are not sufficiently promising and effective. We have identified a novel target to treat AD and can show evidence that developing drugs against this target will improve both the symptoms as well as repair or protect against the brain damage caused by this disease. This project is important in order to validate the target, then to actually make new drugs that are the most selective for this target, and then to test these drugs in an animal model of the disease, all of which paves the way for human drug development.

The goal of our project is to design, synthesize, and characterize highly selective drugs that activate the alpha1A-adrenergic receptor, and test them in a mouse with Alzheimer’s disease (AD) to see if these new drugs can reverse the disease process or help with symptomatic relief. The alpha1A-adrenergic receptor (alpha1A-AR) regulates stress in the body and neurotransmission in the brain. We are designing at least 10 different drugs that are variations of a starting compound called cirazoline. We previously have shown that cirazoline increases memory functions in normal mice by creating stronger connections in the brain. These 10 new drugs will increase the ability to selectively activate this key receptor by 500 fold versus other types of receptors; thus, reducing any side effects and allowing us to confirm that the alpha1A -adrenergic receptor is a true target to focus on to treat AD in humans.

Our project is novel since we are the first to discover and show proof that the alpha1A -adrenergic receptor is a viable target for AD. The new therapeutics that we are developing, if successful in a mouse, would be patentable. That would encouraging future collaboration from pharmaceutical companies to begin human trials and provide novel tools to the research community for further studies. As we are the major laboratory that worked out how these receptors bind drugs and performed most of the biochemical and physiological studies in mice, this expertise gives us a unique advantage and a high likelihood of success.