Angewandte Chemie International Edition

Cover image for Vol. 55 Issue 50

Editor: Peter Gölitz, Deputy Editors: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPhotoChem, ChemPlusChem, Zeitschrift für Chemie

For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (2), 265 - 270

No. 02/2002

Coming Soon:
Less Post-Operative Nausea?

Side-effect-free antagonist
for muscle relaxants:
Neutralization through encapsulation

Patients who undergo operations often receive muscle relaxants. These neuromuscular blockers suppress random muscle movements and reflexes that would cause problems during intubation for respiration while under anesthesia, as well as in surgical procedures on interior organs. In order to lift the neuromuscular blockade after surgery, an antagonist to the blocker is administered to the patient. Unfortunately, these agents cause a number of unpleasant side effects, such as nausea and vomiting, low blood pressure, and lowered heart rate. These then require further medication, which brings along still more side effects.

Scientists working for the Organon company in Scotland wanted to try to remove the muscle block by a completely different method. In collaboration with colleagues at the Universities of Southampton in the UK and Nijmegen in the Netherlands, Ming-Qiang Zhang’s group developed an unconventional strategy, which should cause almost no side effects. Instead of constantly interfering with physiological pathways, the idea was to simply "recapture" the blocker molecules that are no longer necessary, and to render them ineffective by "packaging" them. But what material to use for "packaging"? The researchers chose cyclodextrins as their starting material. These ring-shaped polysaccharides consisting of six, seven, or eight glucose building blocks can enclose molecules. They have previously been successfully used to increase the stability and biological availability of poorly water-soluble pharmaceuticals.

In fact, rocuronium, the neuromuscular blocker used in the experiments, fits quite nicely into the eight-membered cyclodextrin; the bulging ring has just the right diameter. However, the rim is a bit too narrow to allow the rocuronium molecule to completely disappear into the interior. In order to further improve the fit, Zhang and co-workers attached side chains to the cyclodextrin ring.

Org25969, as the modified ring is called, now optimally encapsulates the blocker. In animal trials, Org25969 was able to normalize muscle contractions blocked by Rocuronium by 90% within only three minutes. No side effects were observed. Now the "synthetic receptor" has to prove itself in currently ongoing human clinical trials.