Molecular containers for the sequestration of neurotransmitter drugs in
water

Date:
June 17, 2020
Source:
Wiley
Summary:
Molecular containers that remove drugs, toxins, or malodorous
substances from the environment are called sequestering
agents. Scientists have developed a class of molecular containers
that specifically sequester neurotransmitter antagonists. The
barrel-shaped molecules called Pillar [n]MaxQ bind neuromuscular
blocking chemicals 100,000-fold more tightly than established
macrocyclic detoxification agents, the researchers report.



FULL STORY ========================================================================== Molecular containers that remove drugs, toxins, or malodorous substances
from the environment are called sequestering agents. Scientists have
developed a class of molecular containers that specifically sequester neurotransmitter antagonists. The barrel-shaped molecules called
Pillar[n]MaxQ bind neuromuscular blocking chemicals 100,000-fold
more tightly than established macrocyclic detoxification agents, the researchers report in the journal Angewandte Chemie.


========================================================================== Molecular containers of the cyclodextrin type sequester their targets
by complexation. The ring- or barrel-shaped molecules recognize the
molecular features of the target molecules and pull them into the central cavity using hydrophobic forces. Once the target molecule is inside this molecular container, it is neutralized. This host-guest complexation
is the mechanism by which cyclodextrins, which are large, ring-shaped
sugar molecules, eliminate unpleasant odors.

However, cyclodextrins are not very specific and fail for most alkaloids
-- a class of nitrogen-containing chemicals, including neurotransmitters
and many illicit drugs. For these compounds, a class of molecular
containers called pillararenes appear to be useful. They keep the
alkaloids tightly bound in their pillararene cavity by wrapping a ring
wall of aromatic benzene units around the hydrocarbon-rich molecular body.

Lyle Isaacs and his research team from the University of Maryland have
further advanced the structure of the pillararenes to make the host-guest interactions stronger and more specific. "We envisioned to create a higher negative charge density around the mouth of the cavity by introducing
acidic sulfate functional groups," the authors wrote. The negatively
charged sulfate groups attract and bind quaternary ammonium ions, which
are a hallmark of several clinically important neuromuscular blocking
agents. The sulfate groups also stiffened the molecular structure of
the barrels, the researchers found, so that the drug guest was smoothly
pulled into the cavity by hydrophobic forces.

The researchers dubbed the molecular containers Pillar[n]MaxQ, where
n indicates a target-size-dependent diameter that is variable. They
observed that this class of sequestering agents binds the neuromuscular blockers up to 100,000-fold more tightly than the cyclodextrin container Sugammadex, which is in clinical use. Moreover, the sequestering agent discriminated against acetyl choline, a natural transmitter substance
of nerve impulses within the central and peripheral nervous systems,
which should not be sequestered.

The authors measured the host-guest complexation activities of
Pillar[n]MaxQ by titration studies involving calorimetry and nuclear
magnetic resonance of the guest molecules. As pillararenes have also
been shown to reverse the effects of neuromuscular agents in rats,
the researchers are aiming to study the new Pillar[n]MaxQ sequestering
actions in animal models. Because of the high binding and the specificity
of the chemically tailored molecular containers, they are confident that
they will observe positive results.


========================================================================== Story Source: Materials provided by Wiley. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Weijian Xue, Peter Y. Zavalij, Lyle Isaacs. Pillar[ n ]MaxQ:
A New High
Affinity Host Family for Sequestration in Water. Angewandte Chemie
International Edition, 2020; DOI: 10.1002/anie.202005902 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200617102434.htm

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