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Richard B. Mailman

Richard B. Mailman

Professor, Pharmacology

Primary Location
7922 Suhling Wing, West Medical Campus
Charlottesville, Virginia
Primary Phone Number
353.86.
Email
[email protected]

Bio & Overview

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.

Academic Information

Department
Pharmacology

Primary Education

  • BS, Food chemistry, Rutgers University, 1968
  • MS, Physiology, North Carolina State Univeristy, 1972
  • PhD, Physiology, North Carolina State University, 1974

Research Interests

Dopamine receptor drug discovery, signaling, function, and clinical translation. The effect of environmental agents on brain disorders.

Research Disciplines

  • Alzheimer's Disease
  • Cell and Developmental Biology
  • Molecular Pharmacology
  • Neuroscience
  • Psychiatry and Neurobehavioral Sciences

Selected Publications

Recent Publications

Mailman RB, Huang X. Hot Topic: Dopamine D1 agonists and cognition: a new frontier in neuropsychopharmacology. Neuropsychopharmacology [in press]

Bransom l, Bassett ap, Zhou m, Mailman RB, Yang Y. Concomitant activation of D1 dopamine and α2A adrenergic receptors improves cognition better than methylphenidate in two rodent behavioral tests. Discov Pharm Sci. 2026;2(1):11. doi: 10.1007/s44395-026-00047-3. Epub 2026 Jun 18. PMID: 42394854

Bassett AP, Bransom L, Mailman RB, Yang Y. Effect of Functionally Selective Dopamine D1 Receptor Agonists on Complex Cognitive Processes in a Rodent Touchscreen Operant Chamber Task. eNeuro. 2026 May 19;13(5):ENEURO.0296-25.2026. doi: 10.1523/ENEURO.0296-25.2026. PMID: 42055918

Lewis MM, Mailman RB, Cheng XV, Du G, Zhang L, Li C, De Jesus S, Tabbal SD, Li R, Huang X. Clinical progression of Parkinson's disease in the early 21st century: Insights from the accelerating medicine partnership (AMP-PD) data. Parkinsonism Relat Disord. 2025 Jan;130:107186. doi: 10.1016/j.parkreldis.2024.107186. Epub 2024 Nov 2. PMID: 39541725

De Jesus S, Daya A, Blumberger L, Lewis MM, Leslie D, Tabbal SD, Dokholyan R, Snyder AM, Mailman RB, Huang X. Prevalence of Late-Stage Parkinson's Disease in the US Healthcare System: Insights from TriNetX. Mov Disord. 2024 Sep;39(9):1592-1601. doi: 10.1002/mds.29900. Epub 2024 Jul 4. PMID: 38962960.

Lee EY, Kim J, Prado-Rico JM, Du G, Lewis MM, Kong L, Yanosky JD, Eslinger P, Kim BG, Hong YS, Mailman RB, Huang X. Effects of mixed metal exposures on MRI diffusion features in the medial temporal lobe. Neurotoxicology. Dec;105:196-207. Epub 2024 Oct 11. PMID: 39395642.

Sha CM, Wang J, Mailman RB, Yang Y, Dokholyan NV. Quantifying network behavior in the rat prefrontal cortex. Front Comput Neurosci. 2024 Aug 29;18:1293279. PMID: 39268151; PMCID: PMC11390430.

Bransom L, Bassett AP, Zhou M, Cimino JX, Mailman RB, Yang Y. Dopamine D1 Receptor Agonists Rescue Age-related Decline in Temporal Order Memory. Neuroscience. 2024 Jul 23;551:177-184. doi: 10.1016/j.neuroscience.2024.05.033. Epub 2024 May 31. PMID: 38823551; PMCID: PMC11246218.

Lewis MM, Van Scoy LJ, De Jesus S1, Hakun J, Eslinger E, Fernandez-Mendozo J, Kong L, Yang Y, Snyder B, Loktionova L, Duvvuri S, Gray DL, Huang X, Mailman RB. Dopamine D1 agonists: first potential treatment for late-stage Parkinson’s disease. Biomolecules 2023, 13(5), 829; https://doi.org/10.3390/biom13050829 - 12 May 2023. PMID: 37238699 PMCID: PMC10216182

Han F, Liu X, Mailman RB, Huang X, Xiao Liu. Huang Resting-state global brain activity affects early β-amyloid accumulation in default mode network. Nature Commun. 2023 Nov 27;14(1):7788. doi: 10.1038/s41467-023-43627-y. PMID: 38012153. PMCID: PMC10682457

Chen J, Vishweshwaraiah YL, Mailman RB, Tabdanov ED, Dokholyan NV. A noncommutative combinatorial protein logic circuit controls cell orientation in nanoenvironments. Sci Adv. 2023 May 26;9(21):eadg1062. doi: 10.1126/sciadv.adg1062. Epub 2023 May 26. PMID: 37235645 PMCID: PMC10219599.

Cimino JX, Zhou M, Waxmonsky J, Mailman RB, Yang Y. Characterization of behavioral changes in T-maze alternation from dopamine D1 agonists with different receptor coupling mechanisms Psychopharmacology 2023. online https://doi.org/10.1007/s00213-023-06440-5. PMID: 37578525. PMCID: PMIC10693963.

Yang Y, Kocher SD, Lewis MM, Mailman RB. Dose-Dependent Regulation on Prefrontal Neuronal Working Memory by Dopamine D1 Agonists: Evidence of Receptor Functional Selectivity-Related Mechanisms. Front Neurosci. 2022 Jun 16;16:898051. doi: 10.3389/fnins.2022.898051. eCollection 2022. PMID: 35784852

Yang Y, Lewis MM, Kong L, Mailman RB. A dopamine D1 agonist versus methylphenidate in modulating prefrontal cortical working memory. J Pharmacol Exp Ther. 2022 Aug;382(2):88-99. doi: 10.1124/jpet.122.001215. Epub 2022 Jun 5. PMID: 35661631

Yang Y, Lewis MM, Huang X, Dokholyan NV, Mailman RB. Dopamine D1 receptor-mediated β-arrestin signaling: Insight from pharmacology, biology, behavior, and neurophysiology. Int J Biochem Cell Biol. 2022 Jul;148:106235. doi: 10.1016/j.biocel.2022.106235. Epub 2022 Jun 7. PMID: 35688404 PMCID: PMCID: PMC10266066.

Noteworthy earlier papers

Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BR, Christopoulos A, Sexton PM, Miller K, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology (Perspective in Pharmacology). J Pharmacol Exp Ther 320: 1-13. PMID: 16803859

Mailman RB, Huang X, Nichols DE (2001) Parkinson's disease and D1 dopamine receptors. Curr Opin Investig Drugs 2(11) 1582-1591.

Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB (1999) Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacol. 20:612-627.

Mailman RB, Nichols DE (1998) Dopamine D1 receptor agonists as antiparkinson drugs. Trends Pharmacol Sci. 19: 255-256.

Taylor JR, MS Lawrence, DE Redmond, Jr., JD Elsworth, RH Roth, DE Nichols, Mailman RB (1991) Dihydrexidine, a full dopamine D1 agonist, reduces MPTP-induced parkinsonism in African green monkeys. Eur. J. Pharmacol. 199: 3