Template synthesis: double calixarenes bind neuromuscular blockers
Under anesthesia, patients are often given muscle-relaxing
neuromuscular blockers to make intubations easier and reduce the
skeletal muscle tone during surgery. Using a drug to remove the blocking
agent after the operation improves patient recovery and reduces the
risk of complications. In the journal Angewandte Chemie, a
Canadian research team has now reported a novel broad-spectrum antidote.
It consists of two “chalices” that are linked together and cover the
two ends of the blocker.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Neuromuscular blockers are drugs that inhibit the transmission of
stimuli to the synapses between nerves and muscles by blocking the
acetylcholine binding sites on the nicotinic acetylcholine receptors.
Different types of blockers meet different pharmacological needs.
Antidotes in this class are “drugs that bind other drugs,” capturing
free blockers in the blood stream and reversing the blockade.
Until now, most “unblockers” have been donut-shaped molecules that
encircle the rod-shaped blockers. For this to work the donut hole must
be tailored for the thickness of the “rod”—which isn't the same for all
types of blocker. Different blockers require different donuts. However,
the blockers do share a rodlike structure with two positively charged
ends (amino groups), and the rods are all of equal length, because they
must simultaneously bridge the gap between two opposite acetylcholine
binding cavities.
A team at the University of Victoria (Canada) devised a novel
approach to make an unblocking agent that can bind a broad spectrum of
blockers. Instead of having the rods threaded through a hole, the
blocker shields both ends of the rod.
Fraser Hof and his team created cup-shaped molecules known as calix[4]- or calix[5]arenes (calix
= chalice). They attached negatively charged groups to the upper rims
of the “chalice”. Such molecular cups will take up positively charged
molecules like the ends of the blocker rod—but unspecifically. To attain
selectivity for the blockers, the team wanted to attach two cups to
each other by means of a linking segment with a length that exactly
matches that of the rod in question—putting the two cups neatly over the
two ends.
Because the link needed to be very short, there was repulsion between
the two negatively charged chalice rims. The solution was to use a
blocker rod as a “template”. The team put reactive groups on the
chalices and let them bind to a typical blocker. They then used a
suitable linker (hydrazine) to tie together the two cups bound to the
same blocker rod.
The “double chalices”—Super-sCx4 and Super-sCx5—bind to a broad
spectrum of neuromuscular blockers with high selectivity but do not
block acetylcholine and other physiologically important amines.
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About the Author
Dr. Fraser Hof is a
Professor of Chemistry at the University of Victoria, Canada. He works
in supramolecular and medicinal chemistry, making new bioactive
molecules and bioreagents that target diverse problems in human health
by using host molecules that recognize and bind specifically to their
molecular targets. He is also Director of the Centre for Advanced
Materials and Related Technology (CAMTEC).
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