Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats

Ganapati, S. V.; Grabitz, Stephanie D.; Murkli, Steven; Scheffenbichler, Flora T.; Rudolph, Maíra I.; Zavalij, Peter Y.; Eikermann, Matthias; Isaacs, Lyle

doi:10.1002/cbic.201700289

Cited by 65 publications

(54 citation statements)

References 46 publications

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“…We envisioned that 27 would bind to methamphetamine in the bloodstream and induce a negative concentration gradient from the brain and thereby modulate the hyperlocomotion induced by methamphetamine. [46] Using a combination of 1 H NMR, UV/Vis, and isothermal titration calorimetry (competition) assays we measured the binding affinity of seven drugs (methamphetamine, fentanyl, cocaine, ketamine, phencyclidine, morphine, hydromorphone) toward several containers ( 26 , 27 , CB[7], HP-β-CD, and 4-sulfo calix[4]arene (SC4A)). We find that 26 and 27 display a broad affinity toward the drugs of abuse with K a values in the 10 4 – 10 7 M −1 range whereas HP-β-CD and SC4A bound more weakly.…”

Section: Acyclic Cb[n]-type Receptorsmentioning

confidence: 99%

Acyclic Cucurbit[n]uril‐type Receptors: Preparation, Molecular Recognition Properties and Biological Applications

Ganapati

Isaacs

2017

Israel Journal of Chemistry

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This article traces the development of acyclic cucurbit[n]uril-type receptors with a focus on work from the Isaacs group. First, we describe the synthesis of methylene bridged glycoluril dimers capped with aromatic sidewalls which allowed us to probe the interconversion of the S- and C-shaped dimers which is a fundamental step in CB[n] formation. The C-shaped compounds were found to undergo discrete self-assembly (dimerization) in both water and organic solvents which lead us to investigate multicomponent self-sorting systems. We supressed the self-association of by electrostatic repulsion in the putative dimer which allowed expression of its innate molecular recognition properties toward methylene blue and related planar cationic dyes. Longer glycoluril oligomers (trimer - hexamer, acyclic decamer) were prepared by starving the CB[n]-forming reaction of formaldehyde. The longer oligomers (e.g. and ) bind to alkylammonium ions in water ≈ 100-fold weaker than macrocyclic CB[n] highlighting the high preorganization of the acyclic but polycyclic framework. We prepared a wide variety of acyclic CB[n] compounds (wall variants, solubilizing group variants, linker variants) based on glycoluril trimer and tetramer. In particular, and have been shown to possess a wide variety of chemically and biologically interesting functions. For example, was used to formulate the insoluble drug Albendazole and treat mice bearing SK-OV-3 xenograft tumors. Compound binds tightly to the neuromuscular blocking agents rocuronium, vecuronium, and cisatracurium and acts as an reversal agent for these compounds in anesthetized rats. Container was also found to modulate the hyperlocomotive effect of rats that had been treated with methamphetamine. Finally, has been used as a cross reactive component of sensor arrays that are capable of classifying and quantifying cancer related nitroamines and a range of over the counter drugs. Overall, the work demonstrates that acyclic CB[n]-type compounds are nicely pre-organized and therefore retain the essential aspects of the recognition properties of macrocyclic CB[n] but allow for more straightforward tailoring of structure and solubility that enables a variety of chemically and biologically important applications.

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Section: Acyclic Cb[n]-type Receptorsmentioning

confidence: 99%

Acyclic Cucurbit[n]uril‐type Receptors: Preparation, Molecular Recognition Properties and Biological Applications

Ganapati

Isaacs

2017

Israel Journal of Chemistry

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“…In the long term, research into hosts for methyllysines will also benefit from the development of artificial antibodies for similar PTMs, such as methylarginine, methylhistidine and methyladenine . The general concepts found for methyllysine binding will further stimulate the recognition of related guest species, such as methylamines, for example, ecstasy, amphetamines or other illegal substances . Already, synthetic methyllysine receptors have prompted the development of macrocycles for the detoxification of organophosphonates, which can be, and are, misused as chemical warfare agents.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Receptors for the Recognition and Discrimination of Post‐Translationally Methylated Lysines

Gruber

2018

ChemBioChem

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Post-translational modifications (PTMs) describe the chemical alteration of proteins after their biosynthesis in ribosomes. PTMs play important roles in cell biology, including the regulation of gene expression, cell-cell interactions and the development of different diseases. A prominent class of PTMs is the side-chain methylation of lysine. For the analysis and discrimination of differently methylated lysines, antibodies are widely used, although methylated peptide and protein targets are known to be particularly difficult to differentiate by antibody-based affinity reagents; an additional challenge can be batch-to-batch reproducibility. The application of mass spectrometry techniques for methyllysine discrimination requires a complex sample preparation procedure and is not suited for working in cells. The desire to overcome the above-mentioned challenges has promoted the development of synthetic receptor molecules that recognise and bind methyllysines. Such "artificial antibodies" are of interest for a number of applications, for example, as reagents in biochemical assays, for the isolation and purification of post-translationally methylated proteins and for the tracking of signalling pathways. Moreover, they offer new approaches in diagnostics and therapy. This review delivers an overview of the broad field of methyllysine binding and covers a wide range of synthetic receptors used for the recognition of methylated lysines, including calixarenes, resorcinarenes, pillararenes, disulfide cyclophanes, cucurbiturils and acyclic receptors.

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“…The complexation of various illicit drugs (methamphetamine, fentanyl, cocaine, ketamine, phencyclidine, morphine and hydromorphone, Figure 1 B) by CLBD1, CLBD2, and other host molecules (CB 7 , C[4]AS and HP- β -CD) was investigated. Among all hosts, CLBD2 showed a good binding affinity for methamphetamine ( K a = (4.3±1.0)×10 6 M -1 , Figure 7 ), enabling to reverse the hyperlocomotive activity of rats treated with methamphetamine 81 .…”

Section: Acyclic Cucurbiturilsmentioning

confidence: 99%

Recent advances in supramolecular antidotes

Yin¹,

Zhang²,

Wei³

et al. 2021

Theranostics

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Poisons always have fascinated humankind. Initially considered as deleterious or hazardous substances, the modern era has witnessed the controlled utilization of dangerous poisons in medicine and cosmetics. Simultaneously, antidotes have become crucial as reversal agents to counteract the effects of a poison, and they are also used today to positively cancel the benefits of a poison after use. Currently, the majority of poisons are composed of small molecules. This review focuses on recent developments to reverse or prevent toxic effects of poisons by encapsulation in host molecules. Cyclodextrins, cucurbiturils, acyclic cucurbituril derivatives, calixarenes, and pillararenes, have been reported to largely impact the effects of toxic compounds, thus extending the current paradigm of small molecule antidotes by adding a new family of macrocyclic compounds to the current arsenal of antidotes. Along this line of research, endogenous "harmful" species are also sequestered by one or more of these supramolecular host molecules, expanding the potential of supramolecular antidotes to diverse therapeutic areas.

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Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats

Cited by 65 publications

References 46 publications

Acyclic Cucurbit[n]uril‐type Receptors: Preparation, Molecular Recognition Properties and Biological Applications

Acyclic Cucurbit[n]uril‐type Receptors: Preparation, Molecular Recognition Properties and Biological Applications

Synthetic Receptors for the Recognition and Discrimination of Post‐Translationally Methylated Lysines

Recent advances in supramolecular antidotes

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