Dissertations, Theses, and Capstone Projects

Date of Degree

9-2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Chemistry

Advisor

Wayne W. Harding

Committee Members

David R. Mootoo

Shengping Zheng

Mark R. Biscoe

Subject Categories

Medicinal-Pharmaceutical Chemistry | Organic Chemistry

Abstract

Dopamine regulates motor control, cognition, reward, motivation, and neuroendocrine signaling. Disruption of dopaminergic neurotransmission is closely linked to central nervous system disorders, including Parkinson’s disease, schizophrenia, addiction, and related neuropsychiatric conditions. Because these functions are mediated by multiple dopamine receptor subtypes with distinct roles in physiology and disease, the discovery of subtype-selective ligands remains an important goal in neuropharmacology. Within this context, protoberberine alkaloids, particularly tetrahydroprotoberberines (THPBs), are attractive molecular frameworks because they combine structural complexity with broad biological relevance, including measurable activity in CNS-related diseases. Prior work from our laboratory and others established (–)-stepholidine (1.60) as an important lead because of its dopaminergic profile and its value as a template for dopamine receptor ligand design. Along with (–)-isocorypalmine (2.80), it illustrates both the promise and the limitations of this class of natural products: these compounds show meaningful dopaminergic activity, but their structural complexity has historically limited analogue synthesis, and phenolic groups are susceptible to metabolic liabilities that can restrict further development. Our work addresses these limitations by developing efficient synthetic methodologies, natural product synthesis, and dopamine receptor ligand design. We developed a one-pot copper-catalyzed decarboxylative olefination cascade as a unified and efficient strategy for the synthesis of 8-oxoprotoberberine frameworks from dihydroisoquinoline and homophthalic anhydride precursors. This method merges annulation and copper-mediated decarboxylative olefination into a single sequence, providing direct access to highly functionalized 8-oxoprotoberberines under milder conditions. In contrast to earlier approaches, which often relied on multistep cyclizations, harsh reaction conditions, and limited regioselective control, our synthetic strategy offers clear advantages in step economy, modularity, functional-group tolerance, and late-stage diversification. Its value was demonstrated not only in substrate-scope studies but also in concise total syntheses of important alkaloids. Berberine (2.10) was prepared in 42% overall yield in six steps, compared with earlier routes that required more than eight steps and delivered less than 35% overall yield. Similarly, (±)-isocorypalmine (2.80a) was synthesized in eight steps and 28% overall yield, whereas earlier methods required more than ten steps and provided less than 20% overall yield. For (±)-stepholidine (1.60a), our route furnished the target in nine steps and 18% overall yield, while previous approaches required more than fifteen steps and delivered less than 25% overall yield. Mechanistic experiments further supported a copper-mediated radical decarboxylative process underlying the key olefination step. Our work further explored the structural modification of (-)-isocorypalmine (2.80) as a scaffold for dopamine receptor ligands, with particular emphasis on dopamine D3 receptor selectivity in the broader context of dopamine-related CNS disorders. (-)-Isocorypalmine (2.80) was selected as a lead scaffold because it retains the rigid framework needed for

dopamine receptor recognition, shows meaningful affinity across dopamine receptor subtypes, and exhibits behavioral effects relevant to dopaminergic dysfunction. At the same time, the phenolic hydroxyl group of (-)-isocorypalmine was recognized as both a contributor to receptor binding and a likely metabolic liability. We therefore designed a focused series of C2-modified analogues using phenolic bioisosteric replacement, with the goal of preserving favorable receptor interactions while reducing susceptibility to rapid conjugative metabolism. Biological evaluation showed that this approach was successful only for selected bioisosteric classes and clearly identified sulfonamides as the most effective phenolic replacements in this series. In contrast to amides, thioureas, and thiazoles, sulfonamide analogues preserved useful dopamine receptor affinity and shifted the parent scaffold toward a D3-directed profile, primarily by attenuating D1 receptor affinity to a much greater extent than D2 or D3 receptor affinity. Several sulfonamide analogues displayed nanomolar D3 receptor affinity together with improved D3/D2 selectivity, with the most favorable results arising from selected aryl, fused aryl, and sulfur-containing heteroaryl substituents. Among the compounds prepared, analogues 4.15o, 4.15s, and 4.15aq emerged as the most promising compounds, showing high D3 receptor affinity in the series together with measurable selectivity over D2 and very weak affinity at D1. These findings show that phenolic bioisosteric replacement is not only a useful metabolic optimization strategy but also an effective means of redirecting this natural product framework toward a more selective dopamine receptor subtype. Replacement of the C2 phenolic group significantly improved the dopaminergic profile of the series, consistent with the original design hypothesis. Preliminary functional activity characterizations on the prototype ligand 4.15o indicate that it is a D3/D2 receptor antagonist with >70-fold selectivity over D1R. The lead sulfonamide analogue 4.15o showed improved rat liver S9 metabolic stability relative to parent (-)-isocorypalmine, along with excellent chemical stability and favorable BBB-penetration. These results directly address one of the major drawbacks associated with phenolic tetrahydroprotoberberine natural products and provide a more drug-like platform for future ligand optimization. Overall, our work demonstrates that protoberberine alkaloids are valuable scaffolds at the interface of synthetic organic chemistry and dopamine receptor ligand discovery. It provides an efficient catalytic platform for the synthesis of oxidized and reduced protoberberine frameworks, expands access to important natural products such as berberine (2.10), (±)-isocorypalmine (2.80a), and (±)-stepholidine (1.60a), and identifies bioisosterically modified (-)-isocorypalmine analogues as promising D3-directed ligands with improved stability profiles. More broadly, our work provides enabling chemistry for future studies by making these frameworks more accessible, more modular, and more suitable for analogue generation and structure–activity relationship investigations. In this way, it advances both the chemistry of protoberberine alkaloids and their potential utility in the development of new therapeutics for dopamine-related CNS disorders.

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