The recreational use of drugs of abuse is a major problem worldwide; overdoses and the associated mortality are common. Therefore, the development of treatments for overdose and addiction of drugs such as 6 - 12 (Figure 1) is an important biomedical problem with significant socio-economic consequences. Current treatment strategies aim to either disrupt the binding of the drug to its receptor (pharmacodynamic strategy – PD) or to decrease drug concentration below its effective concentration (pharmacokinetic strategy – PK). The molecular recognition properties of containers such as cyclodextrins and cucurbit[n]urils (CB[n]) have been previously used to implement the PK strategy to directly compete with biological molecular recognition events. The γ-cyclodextrin derivative Sugammadex (marketed worldwide by Merck under the trade name BridionTM) has been shown to bind with high affinity (≈ 107 M-1) toward the neuromuscular blocking agents rocuronium and vecuronium in vitro and to act as an reversal agent for neuromuscular block in vivo. Accordingly, we decided to evaluate the potential of some well known, water soluble (&gt; 10 mM) molecular containers as agents for the in vivo reversal of the biological effects of drugs of abuse by the PK strategy. In this study, we have measured the thermodynamic binding constants of molecular containers 1 – 5 with illicit drugs 6 - 12 by 1H NMR, UV/ Vis and ITC based assays; and found that they span from less than 102 to over 108 M-1. We also find that 2, but not CB[7], is able to modulate the increased hyperlocomotive activity of rats treated with methamphetamine.

Molecular containers bind drugs of abuse in vitro and reverse the hyperlocomotive effect of methamphetamine in rats

254th National Meeting (2017)

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