Funding Award Enables First Study to Examine Cognitive Effects of an Alpha-1 Agonist

Cleveland Clinic researcher Dianne Perez, PhD, has been named the Alzheimer’s Drug Discovery Foundation (ADDF)-Harrington Discovery Institute Scholar for her promising research in Alzheimer’s disease (AD). The annual award provides up to $600,000 in project funding over two years, which she will use to evaluate the cognitive effects of a compound she has spent nearly 30 years researching and developing.

An unexpected discovery

Dr. Perez, a staff scientist in the Department of Molecular Cardiology in Cleveland Clinic Lerner Research Institute, has spent most of her career elucidating the causes of and investigating new therapeutics for vascular diseases. So it was an interesting surprise when she discovered that a compound she was developing to protect against cardiac ischemia had significant benefits on cognition, learning and memory in mice.

A target for ischemia becomes a potential target for AD

Her original research focused on understanding the structure and function of a class of molecules called G-protein-coupled receptors (GPCRs). Her lab was particularly interested in one type of GPCRs, alpha-1 adrenergic receptors, which bind to the neurotransmitters norepinephrine and epinephrine.

These specific interactions were of interest because epinephrine causes blood vessels to narrow, increasing blood pressure, and adapts the heart to withstand damage, which could make it a viable treatment strategy for ischemia. Dr. Perez set out to develop an agonist compound that could imitate and amplify this norepinephrine/epinephrine-receptor binding.

She discovered that overexpression of alpha-1B adrenergic receptors caused seizures, vascular complications, apoptosis and neurodegeneration, while an abundance of alpha-1A adrenergic receptors had profound cardio- and neuroprotective effects.

Remarkably, mice with overexpressed alpha-1A adrenergic receptors had reduced risk of ischemia and cancer, lived 10 to 15 percent longer, and showed signs of improved cognition. They exhibited enhanced learning and memory as well as increased neurogenesis and synaptic plasticity. This finding led Dr. Perez to hypothesize that alpha-1A adrenergic receptor agonists could potentially be used as a treatment for AD.

Designing a smarter compound

Over the years, alpha-1 agonists have waned in popularity due to serious side effects. Dr. Perez set out to design a smarter drug that could uncouple the cognitive benefits she observed from the potentially harmful effects on blood pressure.

She and her team synthesized one particular compound, dubbed “compound 3,” which did just that. It had the desired effects on learning, memory and brain cell function without raising blood pressure.

Compound 3 — an agonist-like compound — is an allosteric modulator, binding receptors at different sites than its natural ligands. This causes more selective binding and signaling. Compound 3 favors norepinephrine binding in the brain and amplifies cAMP signaling (a GPCR-triggered signaling pathway) rather than epinephrine binding and calcium signaling throughout the peripheral nervous system, which leads to the increased blood pressure characteristic of agonists.

Preclinical testing of compound 3 proceeds

With the support of the new ADDF-Harrington Scholar Award, Dr. Perez has begun testing the effects of compound 3 in a preclinical model of AD.

“I am deeply grateful for this honor,” says Dr. Perez. “The ADDF-Harrington Scholar Award helps support research at a critical point in the research continuum — during early phases when scientists are collecting the data needed to secure larger grants and clinical collaborations. I thank the funding organizations for making this project possible and helping us take our work to the next level, where we can hopefully one day impact patients.”

Following this phase of the project, Dr. Perez plans to find ways to optimize compound 3 (which is patented by Cleveland Clinic) before pursuing clinical trials in individuals with or at risk for AD.

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