An innovative macroring material can trap a variety of drugs in overdose cases, including opioids, hallucinogens and stimulants, thanks to its hydrophobic niche
[Translation by Dr. Moshe Nachmani]
![The macrocyclic compound P6AS can trap a variety of drugs that can cause overdose, including opioids, hallucinogens and stimulants, thanks to a hydrophobic internal niche. [Courtesy: © Brockett et al., Chem 9, 1–20 April 13, 2022 Elsevier Inc]](https://www.hayadan.org.il/images/content3/2023/01/fx1.jpg.webp)
A macrocyclic compound has been shown to be promising as a broad-spectrum antidote in cases of drug overdose, including opioids, hallucinogens and stimulants, some without any existing treatment, for example methamphetamine and phencyclidine. The compound from the pillararene family, known as P6AS, can store drug molecules inside it and change their properties, thereby reducing mortality following drug overdose.
Opioid overdoses, including heroin and fentanyl, are currently treated with the help of the small molecule Naloxone which blocks the receptors involved in the process. However, this drug is not effective in cases of non-opiate drugs. Antibodies were also tested as treatments against possible overdoses, after studies showed that they bind strongly to drugs in the bloodstream, including cocaine and methamphetamine, and prevent their passage through the blood-brain barrier. Despite this, antibodies are expensive substances to prepare, require storage under controlled conditions and are exposed to degradation over time.
Now, researchers at the University of Maryland are taking advantage of host-guest chemistry to find a potential, broad-spectrum treatment against overdoses. "Our compounds are produced with the help of synthetic organic chemistry in the framework of a short synthesis that includes three steps, a synthesis that is not expensive and can be easily scaled up to large quantities" says the lead researcher. "Furthermore, our compounds have very good solubility in water, as well as high chemical and thermal stability."
The researchers focused on compounds from the pillarene family - macrocyclic compounds that form host-guest structures - in light of the fact that studies in recent decades have shown that these compounds reverse the effects of anesthetics and pesticides. In addition, the researchers found in 2020 that pylaranes that have been attached to sulfate groups bind more strongly to hydrophobic cations in water. Many drugs contain hydrophobic cations in their structure, so the researchers thought that the filaranes might simply be able to trap and flush these drugs out of the bloodstream.
In order to test this theory, the researchers tested the binding affinity of four pilaranes with a range of drugs, including methamphetamine, fentanyl, MDMA (ecstasy), PCP, and mephedrone. The results proved that these drugs all bind to pilarans in water, especially with strong binding to the P6AS compound. "It was a positive surprise to see that the compound P6AS binds strongly to a wide variety of drugs that can be given in overdoses, which provides real potential as a conflicting agent in the field of drug poisoning," explains the lead researcher.
The compound P6AS is a ring compound built from six "walls" of phenylenes that include 12 modifiers that form a ring niche around a hydrophobic compound. This structure allows the compound to bind to hydrophobic cations, through a combination of the hydrophobic effect and pi (π) non-covalent interactions between the aromatic rings of the drugs and the walls of the host compound as well as ion-ion electrostatic interactions between the sulfate groups and the ammonium ion of the drug .
Experiments in vitro verified that indeed the compound P6AS does not cause mutations in cells or that it inhibits the normal passage of ions in ion channels, an important passage for the heart's activity. The research team also determined the maximum dose of the compound that can be taken safely in the BAH. Experiments on mice given methamphetamine or fentanyl showed that the narcotic effects were reversed when the mice received injections of the compound P6AS within five to fifteen minutes later.
"Finding an application for everyday life, ideally one related to clinical or consumer use, requires testing the acidity in the development of different groups of macro-rings, and usually requires the development of water-solubility profiles," explains one of the experts in the field. "The current research about the phyllarans is such a big breakthrough, following pioneering applications about other macrorings. The high affinity of pylaranes containing sulfate groups to methamphetamine as well as fentanyl is quite interesting."
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