Under anesthesia, patients are often given neuromuscular muscle relaxant blockers to facilitate intubations and reduce 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 review Angewandte Chemie, a Canadian research team has now reported a new broad-spectrum antidote. It consists of two “chalices” which are linked together and cover both ends of the blocker.
Neuromuscular blockers are drugs that inhibit the transmission of stimuli to synapses between nerves and muscles by blocking acetylcholine binding sites on nicotinic acetylcholine receptors. Different types of blockers meet different pharmacological needs. Antidotes in this class are ‘drugs that bind to other drugs’, capturing free blockers in the bloodstream and reversing the blockage.
Until now, most “unlockers” have been donut-shaped molecules that encircle rod-shaped blockers. For this to work, the donut hole needs to be matched to the thickness of the “shank” – which is not the same for all types of blockers. Different blockers require different donuts. However, the blockers share a rod-shaped structure with two positively charged ends (amino groups), and the rods are all of equal length, as they must simultaneously bridge the gap between two opposing acetylcholine binding cavities.
A team from the University of Victoria (Canada) devised a new approach to making a release agent capable of binding a wide variety of blockers. Instead of having the rods threaded through a hole, the blocker protects both ends of the rod.
Fraser Hof and his team created cup-shaped molecules known as the calix- or chalicearenas (chalice = chalice). They attached negatively charged groups to the upper edges of the “chalice”. Such molecular cuts will take up positively charged molecules like the ends of the blocking rod – but in a non-specific way. To achieve selectivity for blockers, the team wanted to attach two cups to each other by means of a connecting segment with a length that exactly matches that of the rod in question – by placing the two cups carefully on both ends.
Because the bond had to be very short, there was repulsion between the two negatively charged chalice edges. The solution was to use a locking rod as a “template”. The team placed reactive groups on the chalices and allowed them to bind to a typical blocker. They then used a suitable linker (hydrazine) to bind together the two cups linked to the same locking rod.
The “double calyxes” – 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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