Education
Ph.D., University of Groningen, Supervisor Prof. Ben L. Feringa (Nobel Laureate)
The interdisciplinary research conducted in the Arnold Group combines the traditional fields of organic chemistry, biochemistry, analytical chemistry, and pharmacology to develop bioactive probes to investigate the underlying biomolecular pathways of human diseases.
Research Areas
Our research interest has shifted throughout the years and started with development of small molecule inhibitors of the vitamin D receptor – coactivator interaction to regulated transcription. Initial discoveries resulted in a comprehensive research program with a focus on developing new anti-cancer agents. Tools used for this research ranged from high throughput screening and rational drug design to efficacy measurement in vivo using murine cancer models. This work has been described in several publications and patents.
Our interest in respiratory diseases, specifically asthma, started with the support of the NHLBI and collaboration with Prof. James Cook (UWM) and Prof Charles Emala (Columbia). Their pioneer work identified specific GABA(A) receptor subtypes on airway smooth muscle and developed subtypes specific GABA(A) receptor ligands to induce bronchodilation. Our group discovered specific compounds that reduced bronchoconstriction and airway inflammation without adverse CNS effects. These compounds did not cross the blood-brain barrier thus enabling systemic administration with goal of developing a pill for asthma. This work resulted in many publications and patents as well as UWM startup company named Pantherics commercializing this invention.
In collaboration with the NIMH psychoactive drug screening program (PSDP), we observed that some novel benzodiazepine GABA(A) receptor ligands exhibit affinities for other CNS receptors including G-protein coupled receptors. We have published research regarding novel ligands for the opioid receptors and recently introduced new antagonists for the alpha 2 adrenergic receptors based on a benzodiazepine scaffold. We are planning to continue developing new GPCR ligands using the privileged benzodiazepine scaffold that has shown exceptional DMPK (drug metabolism and pharmacokinetics) and applying our synthetic strategies to control brain transit depending on the medical indication.
Ethan T. Kowalczyk, Kayode M. Medubi, Michelle J. Meyer, Mubaraq A. Toriola, Tyler J. Haasch, Makena R. Vesperman, Daniel A. Webb, Douglas C. Stafford, Gene T. Yocum, Charles W. Emala, Leggy A. Arnold “
Development of novel pegylated imidazobenzodiazepines as inhaled asthma drug candidates” Respiratory Medicine, 249, 108449,
2025.Daniel A Webb, Michelle J Meyer, Kayode M Medubi, Anika S Tylek, Gene T Yocum, M S Rashid Roni, Nicolas M Zahn, Sarah A Swartwout, Ahmad K Masoud, Charles W Emala, Douglas C Stafford, Leggy A Arnold “
Design, Synthesis, and Biological Evaluation of Novel Spiro Imidazobenzodiazepines to Identify Improved Inhaled Bronchodilators” J Med Chem,
2023, 66(14), 9853-9865.
M.S. Rashid Roni, Nicolas M. Zahn, Gene T. Yocum, Daniel A. Webb, Md Yeunus Mian, Michelle J. Meyer, Anika S. Tylek, James M. Cook, Charles W. Emala, Douglas C. Stafford and Leggy A. Arnold “
Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer"
Drug Development Research 2022, 83(4), 979-992
Nicolas M. Zahn, M.S. Rashid Roni, Gene T. Yocum, Michelle J. Meyer, Daniel A. Webb, Md Yeunus Mian, James M. Cook, Douglas C. Stafford, Charles W. Emala, and Leggy A. Arnold "
Development of inhaled GABA(A) receptor modulators to improve airway function in bronchoconstrictive disorders" ACS Pharmacology & Translational Science
2022, 5(2), 80-88.
M. S. Rashid Roni, Nicolas M. Zahn, Brandon N. Mikulsky, Daniel A. Webb, Md Yeunus Mian, Daniel E. Knutson, Margaret L. Guthrie, James M. Cook, Douglas C. Stafford, Leggy A. Arnold “
Identification and Quantification of MIDD0301 metabolites” Current Drug Metabolism 2021, 22(14), 1114-1123.
Olivia B. Yu, Daniel A. Webb, Elliot S. Di Milo, Tania R. Mutchie, Kelly A. Teske, Taosheng Chen, Wenwei Lin, Carole Peluso-Iltis, Natacha Rochel, Moritz Helmstädter, Daniel Merk and Leggy A. Arnold, “
Biological Evaluation and Synthesis of Calcitroic Acid”
Bioorganic Chemistry 2021, 116, 105310.
Nicolas M. Zahn, Brandon N. Mikulsky, M. S. Rashid Roni, Gene T. Yocum, Md Yeunus Mian, Daniel E. Knutson, James M. Cook, Charles W. Emala, Douglas C. Stafford, and Leggy A. Arnold “
Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models”
ACS Pharmacology & Translational Science 2020, 3(6), 1381-1390.
Guanguan Li, Amanda N. Nieman, Md Yeunus Mian, Nicolas M. Zahn, Brandon N. Mikulsky, Michael M. Poe, Kashi R. Methuku, Yongfeng Liu, James M. Cook, Douglas C. Stafford, and Leggy A. Arnold “
A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor”
Molecules 2020, 25(17), 3864.
Amanda N. Nieman, Guanguan Li, Nicolas M. Zahn, Md Yeunus Mian, Brandon N. Mikulsky, Dylan A. Hoffman, Taylor M. Wilcox, Alexander S. Kehoe, Ian W. Luecke, Michael M. Poe,
