Novel Drugs against a New Receptor Target to Treat Alzheimer's Disease

Dianne Perez, PhD
The Cleveland Clinic Foundation (Cleveland, OH)

Co-Principal Investigators

Van Doze, PhD
University of North Dakota
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2016272S
Award Type:
Standard
Award Region:
US Midwestern
Dianne Perez, PhD

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

Summary

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.

Details

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.

About the Researcher

My early publications were seminal in the alpha1-adrenergic receptor (alpha1-AR) field, starting with cloning the receptors, determining the correct nomenclature based upon pharmacology, and initially characterizing their signal transduction pathways. After the initial characterization of the alpha1-ARs, I next mapped out the ligand-binding pocket for both agonists, antagonists, and specialized ligands called imidazolines. This collection of work was very useful to the pharmaceutical industry during the 1990s and 2000s, as several drugs were synthesized based upon my structure-function studies to treat conditions such as stress urinary incontinence and benign prostatic hyperplasia. And now the same approach may be useful to treat neurological disorders. My studies were also seminal for providing insight into how these receptors are activated, by showing the specific amino acid residues involved in the activation process, and the discovery of constitutive activity. Several of these amino acid residues have been shown subsequently to be involved in similar mechanisms in other G-protein-coupled receptors. After the structure-function studies, we created unique transgenic mouse models using large fragments of the isogenic promoters to over express wild type and constitutively active alpha1-AR subtypes in all natively expressing tissues. These mouse models are state of the art in the ability to express and characterize subtype-selective signaling and revealed novel physiology and pathophysiology never before associated with these receptors.

Personal Story

Both my husband’s parents developed severe Alzheimer’s disease. We took care of his mother, Carmen, in our home for eight years after his father passed away and saw first hand the progression of the disease, the hull of a person she became, and the toil, hardship, and emotional heartache it brought to our lives. We were very fortunate to have my sister-in-law living next door in our duplex and she came daily to provide care while I worked, but all evenings and nights we were focused on her care. I set up a home monitoring system to watch her when I could not be in sight. She became anxious when night approached and all our outside activities, shopping, and social life needed to be finished by sundown. There were frequent emergency room trips because she commonly forgot to use her walker and fell, sometimes from climbing over the bed rail at night. Also, she could not tell us when she did not feel well, so infections festered. My husband is older than me and is retired, and I see the beginnings of Alzheimer’s disease now in him too. My dream is for my research to be successful and to eventually be used in clinical trials to halt this terrible disease.

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