Theses and Dissertations from UMD
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Item High Affinity Host-Guest Pairs Enable In Vitro and In Vivo Sequestration of Drugs of Abuse(2020) Murkli Jr., Steven Louis; Isaacs, Lyle L.I.; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Molecular containers of diverse structure and binding preferences has led to their incorporation in numerous applications such as drug solubilization, drug delivery, and drug sequestration. A detailed understanding of the binding properties of novel molecular containers can both guide future structural refinement and open up new potential applications.Chapter 1 introduces molecular containers and the associated benefits of their use in the pharmacokinetic approach to drug sequestration. Among these containers, CB[n] show the highest promise due to their high affinity and selectivity for their intended drug target while displaying high levels of biocompatibility. Accordingly, innovations to the CB[n] scaffold has led to the development of acyclic CB[n]-type receptors capable of achieving drug reversal in vivo, although further design can yield sequestration agents with higher potency. Chapter 2 provides a thorough investigation of the binding preferences of CB[8] towards a set of biologically relevant drugs. These findings serve as both a blinded experimental dataset for computational chemists to validate their predictive capability on host-guest interactions and to establish a working knowledge of CB[8] binding preferences for future applications. Chapter 3 puts the aforementioned binding preferences of CB[8] to the test versus a panel of drugs of abuse in a continuation of the efforts outlined in Chapter 1. This study is then translated to the successful in vivo sequestration and prevention of phencyclidine (PCP)-induced hyperlocomotion by a water-soluble CB[8] derivative previously studied in the Isaacs group. Chapter 4 presents a new member of the acyclic CB[n]-type receptor class bearing anthracene terminated walls, M3, that by design is capable of increased binding affinity across a large guest library. This increased binding affinity is elucidated versus a comparator host bearing naphthalene walls, M2, that has been previously used as a sequestration agent for Neuromuscular Blocking Agents, (NMBA’s) and is currently the highest potency acyclic CB[n]-type receptor available. Finally, the fluorescent responsiveness of M3 is investigated to create a sensing array capable of distinguishing 22 guests providing basis for future sensing experiments.Item Functionalized Acyclic Cucurbit[n]uril Molecular Containers as Reversal Agents for Drugs(2017) Ganapati, Shweta; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The study of molecular containers has a prominent place in the scientific literature with many applications, including drug reversal. The clinical use of the cyclodextrin based reversal agent BridionTM has greatly improved the post-operative safety of patients who undergo surgery aided by NMBAs such as rocuronium. Chapter 1 introduces molecular containers, CB[n], and reports the use of the acyclic CB[n] known as Calabadion 2 as a broad spectrum reversal agent for NMBAs in rats. It also proposes the potential use of molecular containers as reversal agents for the treatment of overdose of illicit drugs in the context of available therapies. Chapter 2 establishes that Calabadion 2 displays good to high levels of selectivity toward the NMBAs rocuronium, vecuronium, and cisatracurium both in vitro and based on simulations designed to capture the essence of the biological system. The excretion profile of Calabadion 2 after NMBA reversal in rats was studied by a 1H NMR assay. It is reported that more than 50% of Calabadion 2 is eliminated intact by the kidneys within 1 hour. Chapter 3 establishes that CB[n] based molecular containers - Calabadion 1, Calabadion 2, and CB[7] display higher affinities than p-sulfocalix[4]arene and HP-β-cyclodextrin toward a panel of illicit drugs for which there are currently no USFDA approved pharmacotherapies. Calabadion 2 but not CB[7] is able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The excretion profile of fentanyl and Calabadion 1 post reversal in rats was studied by HPLC and 1HNMR. It is reported that on an average 24 % fentanyl and 40% Calabadion 1 are eliminated by the kidneys within 1 hour. Chapter 4 discusses the synthesis and molecular recognition properties of three new acyclic CB[n] hosts IV-2a – IV-2c which incorporate alkyl linkers of varying lengths- ethyl, hexyl, and decyl; capping one end of Calabadion 1. These hosts were less water soluble than Calabadion 1 due to the loss of two sulfonate groups and did not undergo intermolecular self-association. However, the intramolecular self-inclusion of the alkyl linkers inside the cavity of these hosts led to decreased binding affinities toward guests compared to Calabadion 1.