High Affinity Host-Guest Pairs Enable In Vitro and In Vivo Sequestration of Drugs of Abuse

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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.