# Cucurbituril Type Receptors as Sequestration Agents for Drugs of Abuse

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $373,955

## Abstract

Project Summary. Over 1.25 million emergency department visits occurred in 2011 due to the abuse of illicit
drugs and prescription opioids resulting in an estimated cost to the United States of $37 billion/year in
healthcare costs and $271.5 billion/year overall when crime and lost productivity are included. The majority of
these cases were due to cocaine (40%), heroin (21%), (meth)amphetamines (13%), and PCP (6%) with
numbers rising in recent years for fentanyl, fentanyl analogues, and drugs (e.g. cocaine) laced with fentanyl.
For this reason, the federal government considers the drug abuse (opioid) epidemic to be a national
emergency. Currently, opioid overdose can be treated with the opioid receptor antagonist Naloxone via a
pharmacodynamic (PD) strategy. However, with the rising abuse of fentanyl, Naloxone is becoming much less
effective and multiple doses are often required. Furthermore, there are no current pharmacotherapies for
intoxication with stimulants (e.g. methamphetamine, cocaine, or mephedrone) or for hallucinogens (e.g.
ketamine or PCP) and ER doctors deliver treatments the only target the patient's symptoms. Accordingly, the
development of new pharmacotherapies for the treatment of intoxication with the full range of drugs of abuse
(opioids, stimulants, hallucinogens) is urgently needed.
In contrast to PD strategies which target the opioid receptor, pharmacokinetic strategies target the drug itself
for sequestration and/or catalytic destruction. Cucurbit[n]urils (CB[n]) are molecular container compounds that
possess exceptionally tight binding (Ka routinely in the 106 – 1012 M-1 range) toward hydrophobic cations in
water which renders them a prime platform to create new in vivo sequestration agents for drugs of abuse. In
key preliminary results we have shown that (acyclic) CB[n] bind strongly (Ka > 106 M-1) toward cocaine,
methamphetamine, ketamine, PCP, fentanyl, and oxycodone in vitro and that Calabadion 2 is capable of
reducing the hyper-locomotor activity observed upon treatment of rats with cocaine or methamphetamine. We
propose to systematically vary the structure of the (acyclic) CB[n] receptors to optimize the binding affinity
toward specific drugs of abuse. For example, Calabadions will be prepared with: 1) covalent caps to provide a
2° bind site for pendant functionality, 2) strategically placed SO3- groups to enhance ion-ion and ion-dipole
interactions, 3) enhanced cavity diameters, and 4) extended aromatic walls. New sequestration agents will be
subjected to a series of in vitro toxicology (Cytotoxicity: MTS metabolic and AK release cell death;
Cardiotoxicity: hERG ion channel inhibition; Mutagenicity: Ames test) and in vivo maximum tolerated dose
studies to establish their biocompatibility. Finally, hyperlocomotion assays will be used to determine the in vivo
efficacy of the most promising sequestration agent / drug pairs. Upon completion of the proposed work we
expect at least one sequestration agent will be nominat...

## Key facts

- **NIH application ID:** 10089461
- **Project number:** 5R01GM132345-03
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** LYLE D ISAACS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,955
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089461

## Citation

> US National Institutes of Health, RePORTER application 10089461, Cucurbituril Type Receptors as Sequestration Agents for Drugs of Abuse (5R01GM132345-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10089461. Licensed CC0.

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