Question

The carboxylate groups in sugammadex are linked to the carbohydrate rings by a four-atom linker chain. Suggest whether a shorter or longer chain would make any difference, and whether there are any advantages in having the linker chain used.

Answer 1

Sugammadex is a novel cyclodextrin which acts as scavenger to the neuromuscular agents rucuronium and vecuronium.

It consists 8 identical carbohydrate molecules. The faces of carbohydrate form the interior macrocycle which creates hydrophobic environment and the side chains attached to the eight glucose monomers at the 6-position, extends the depth of the cavity.

Binding force was further enhanced by attaching a negative charge (an anionic carboxylic function) to the end of these side-chains. This creates electrostatic interaction with the positively charged nitrogen of rocuronium and increases binding by locking the steroid into cycldextrin by forming ionic interactions with quarternary ammonium ion of the drug.

Attaching these side-chains elongated the cavity from a depth of 7.9 to 11–12 Å and a diameter of 7.5–8.3 Å. The elongation of the cavity, the whole rocuronium molecule was encapsulated.

The derivatives with negatively charged carboxyls at the rim of the cyclodextrin cavity, had a higher potency because of electrostatic interaction with the quaternary nitrogen of rocuronium (about 7.5 Å ).

One molecule of sugammadex is able to noncovalently bind one molecule of steroidal muscle relaxant.

This binding is further increased by carboxylate acid groups (COO–), which add an additional electrostatic bond interaction with the positively charged nitrogen of the muscle relaxant. No affinity exists to other muscle relaxants, like succinylcholine, mivacurium, atracurium, or cisatracurium.