Mailman, Richard B.
Primary Appointment
Professor, Pharmacology
Education
- BS, Food chemsitry, Rutgers University
- MS, Physiology, North Carolina State Univeristy
- PhD, Physiology, North Carolina State University
Contact Information
7922 Suhling Wing, West Medical Campus
Charlottesville, Virginia
Telephone: 35386
Email: rmailman@virginia.edu
Research Disciplines
Alzheimer's Disease, Cell and Developmental Biology, Molecular Pharmacology, Neuroscience, Psychiatry and Neurobehavioral Sciences
Research Interests
Dopamine receptor drug discovery, signaling, function, and clinical translation. The effect of environmental agents on brain disorders.
Research Description
My research has focused on receptor signaling and its role in disease and therapy. We are especially expert with dopamine receptors. We have led major advances in the discovery of novel drugs for the treatment of psychiatric disorders. We were the first to elucidate the mechanisms of action of aripiprazole, a drug used to treat schizophrenia and mood disorders that has been and is widely used. We determined that its actions at the dopamine D2 receptor involved biased signaling (functional selectivity) and also off-target effects at a few other key serotonin receptors. While working in this research area, an unexpected result in the lab led us to take a fresh look at the treatment of Parkinson’s disease. It was (and still is) generally believed that the key way to get symptomatic relief from PD symptoms has been through activation of dopamine D2 receptors, Our experiment and a fresh study of available evidence led to the novel hypothesis that the most important mechanism was actually activation of the dopamine D1 receptor. We then began a program that discovered and advanced the first brain penetrable full D1 agonist, and used this in rat, primate, and in the clinic to test this hypothesis. Our results led to a major pharma picking up this idea, refining it, and it has now passed four Phase 3 clinical trials and is expected to be on the market in late 2026. Despite these advances, there are still major questions to be investigated. One hypothesis relates to the current gold standard drug for PD called levodopa. Decades ago, several groups had hypothesized that while this drug is irreplaceable in PD, concomitantly it increased disease progression. Two major clinical studies apparently refuted this idea, but we believe that our new evidence suggests that levodopa is, in fact, toxic, and we are doing mechanistic studies to answer this question rigorously. This knowledge, coupled with the D1 agonist now awaiting approval, may result in the first dramatic difference in PD treatment since levodopa came into use in 1968. We have also shown that D1 agonists will work in the most severe parkinsonism in primate animal models and in one small clinical study. We are hoping to be able to do a large clinical study in this group, and also work on the mechanisms why D1 agonists work when no other drug does. Finally, we collaborate with clinical scientists at UVA and elsewhere on studies related to how toxic metal, especially lead, can cause cognitive deficits and other problems in adult who were exposed to what are considered “safe” levels of lead.