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

Abstract

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.