Photo of Alexander (Leggy) Arnold

Alexander (Leggy) Arnold

  • Professor, Chemistry & Biochemistry
  • Director, Milwaukee Institute of Drug Discovery

Education

1998-2002  Ph.D., Organic Chemistry, University of Groningen, Groningen, The Netherlands (advisor: Ben Feringa)
1996-1998
  M.S., Organic Chemistry, University of Groningen, Groningen, The Netherlands (advisor: Ben Feringa)
1995            ERASMUS Scholarship for Research Projects: Organometallic Chemistry and Biotechnology, University of                                            Groningen, Groningen, The Netherlands
1991-1994   Vordiplom, Inorganic and Organic Chemistry, Rheinische-Westfälische Technische Hochschule Aachen, Aachen,                                    Germany

Office Hours

by appointment (arnold2@uwm.edu)

Teaching Schedule

Course Num Title Meets
CHEM 345-001 Organic Chemistry MWF 12:30pm-1:20pm
CHEM 931-003 Advanced Seminar in Analytical Chemistry No Meeting Pattern
CHEM 932-003 Advanced Seminar in Biochemistry No Meeting Pattern
CHEM 934-001 Advanced Seminar in Organic Chemistry No Meeting Pattern

Courses Taught

CHEM 345 Organic Chemistry I, Undergrad/Graduate, Lecture.
CHEM 345 Organic Chemistry II, Undergrad/Graduate, Lecture.
CHEM 488 Advanced Analytical Techniques, Undergraduate Seminar and Lab.
CHEM 541 Bioprocess Chemical Engineering, Undergraduate, Lecture.
CHEM 599 Special Projects in Chemistry; Undergraduate, Independent Study.
CHEM 640 Advanced Survey of Organic Chemistry, Undergrad/Graduate, Lecture.
CHEM 647 Physical Methods in Organic Chemistry, Undergrad/Graduate, Lecture.
CHEM 691 Senior Research (independent study), Undergraduate, Independent Study.
CHEM 692 Senior Research Thesis (independent study), Undergraduate, Independent Study.
CHEM 741 Topics in organic Chemistry, Classics in Total Synthesis, Graduate, Lecture.
CHEM 748 Physical Organic Chemistry, Graduate, Lecture.
CHEM 744 Medicinal Chemistry II, Graduate, Lecture.
CHEM 912 Graduate Seminar
CHEM 931 Advanced Seminar in Analytical Chemistry, Graduate, Seminar.
CHEM 932 Advanced Seminar in Biochemical Chemistry, Graduate, Seminar.
CHEM 934 Advanced Seminar in Organic Chemistry, Graduate, Seminar.
CHEM 990 Research Organic Chemistry, Graduate, Independent Study.
CHEM 993 Research Analytical, Graduate, Independent Study.
CHEM 996 Research Biochemistry Graduate, Independent Study.

Research Interests

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.     

Google Scholar

Current Research Funding

  1. Arnold, A. (PI) “Medical countermeasures to chemical inhalation based on GABAA receptor targeting” NIEHS, R21, (April 2025 – March 2027).
  2. Blecking, A., Benko, A., Arnold, A. “RE-CHARGE STEM-Creating a new, equitable pathway for high school graduates and students who discontinued a STEM program to enter the local STEM workforce” UW innovation grant, Universities of Wisconsin (January 2025- December 2026).

Selected Publications

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.
Maya R. T. Fernando, Alexander B. Vincent, Shaun G. Harrington, Mubaraq A. Toriola, Kayode M. Medubi, Michelle J. Meyer, Daniel A. Webb, and Leggy A. Arnold "Development of novel Alpha 2B adrenergic receptor ligands by using a palladium catalyzed Buchwald Hartwig amination with a brominated benzodiazepine" RSC Med. Chem., 2025
Daniel A. Webb, Zeid Alsudani, Guolin Xu, Peng Gao, and Leggy A. Arnold “Improved 2-Pyridyl Reductive Homocoupling Reaction Using Biorenewable Solvent CyreneTM (dihydrolevoglucosenone)”, RSC Sustainability 2023, 1 (6), 1522-1529.
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) enantiomerDrug 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.
Tania R. Mutchie, Daniel A. Webb, Elliot DiMilo, Leggy A. Arnold "Strategies for the Design of Vitamin D Receptor Ligands". In: Badr M.Z. (eds) Nuclear Receptors. Springer, Cham. 2021, 199-217.
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.
Daniel E. Knutson, M.S. Rashid Roni, Md Yeunus Mian, James M. Cook, Douglas C. Stafford, and Leggy A. Arnold “Improved scale-up synthesis and purification of clinical asthma candidate MIDD0301” Organic Process Research & Development 2020, 24(8), 1467-1476.
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, David Alvarez-Carbonell, James M. Cook, Douglas C. Stafford, Leggy A. Arnold "Targeting nitric oxide production in microglia with novel imidazodiazepines for non-sedative pain treatmentACS Chemical Neuroscience 2020, 11(13), 2019-2013.
M.S. Rashid Roni, Guanguan Li, Brandon N. Mikulsky, Daniel E. Knutson, Md Yeunus Mian,  Nicolas M. Zahn, James M. Cook, Douglas C. Stafford and Leggy A. Arnold "The effects of pH on the structure and bioavailability of imidazobenzo diazepine-3-carboxylate MIDD0301" Molecular Pharmaceutics 2020, 17(4), 1182-1192.
Olivia B. Yu, Tania R. Mutchie, Elliot S. Di Milo and Leggy A. Arnold, “Synthesis and biological evaluation of calcioic acid” Steroids 2020, 154, 108536.
Tania R. Mutchie, Olivia B. Yu, Elliot S. Di Milo, and Leggy A. Arnold "Alternative binding sites at the vitamin D receptor and their ligandsMolecular and Cellular Endocrinology 2019, 485, 1-8.
Nicolas M. Zahn, Alec T. Huber, Brandon Nicholas Mikulsky, Mae Elizabeth Stepanski, Alexander Scott Kehoe, Guanguan Li, Melissa Schussman, M. S. Rashid Roni, Revathi Kodali, James M. Cook, Douglas C. Stafford, Douglas A. Steeber and Leggy A. Arnold "MIDD0301 ‒ A first-in-class anti-inflammatory asthma drug targets GABAA receptors without causing systemic immune suppressionBasic & Clinical Pharmacology & Toxicology 2019, 125, 75-84.
Gloria S. Forkuo, Amanda N. Nieman, Revathi Kodali, Nicolas M. Zahn, Guanguan Li, M. S. Rashid Roni, Michael Rajesh Stephen, Ted W. Harris, Rajwana Jahan, Margaret L. Guthrie, Olivia B. Yu, Janet L. Fisher, Gene T. Yocum, Charles W. Emala, Douglas A. Steeber, Douglas C. Stafford, James M. Cook , and Leggy A. Arnold “A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABA(A) Receptors in the Lung” Molecular Pharmaceutics 2018, 15, 1766-1777.
Kelly A. Teske, Jonathan W. Bogart and Leggy A. Arnold "Novel VDR antagonists based on the GW0742 scaffold" Bioorganic & Medicinal Chemistry Letters 2018, 28, 351-354.  
Kelly A. Teske, Ganesha Rai, Premchendar Nandhikonda, Preetpal Sidhu, Belaynesh D. Feleke, Anton Simeonov, Adam Yasgar, Ajit Jadhav, David J. Maloney, and Leggy A. Arnold “A parallel chemistry approach to identify novel nuclear receptor ligands based on the GW0742 scaffold” ACS Combinatorial Chemistry 2017, 19, 646-656.

UWM Land Acknowledgement: We acknowledge in Milwaukee that we are on traditional Potawatomi, Ho-Chunk and Menominee homeland along the southwest shores of Michigami, North America’s largest system of freshwater lakes, where the Milwaukee, Menominee and Kinnickinnic rivers meet and the people of Wisconsin’s sovereign Anishinaabe, Ho-Chunk, Menominee, Oneida and Mohican nations remain present.   |   To learn more, visit the Electa Quinney Institute website.