NEUROMUSCULAR BLOCKING AGENTS IN SURGERY

Some of the neuromuscular blocking agents that are used in surgery to relax skeletal muscle act on the nicotinic receptors as cholinergic antagonists. Investigations during the nineteenth century into the mode of action of South American arrow poisons derived from curare led to the identification of the neuromuscular blocking properties of the quaternary ammonium salts of a number of alkaloids, principally tubocurarine 3.12. These complex alkaloids provided the lead compounds for the development of neuromuscular blocking agents. The properties of quaternary ammonium salts in this context were quite readily investigated with test animals. An important structural feature that was identified was the distance between the two quaternary nitrogen atoms. Because the quaternary ammonium salts are strongly hydrophilic, they do not cross the blood:brain barrier and hence do not affect the CNS where acetylcholine is also involved as a neurotransmitter. Pancuronium bromide 3.13 is an example in which the steroid framework is used to impose some rigidity on the acetylcholine- like moiety.

Scheme 4 Neighbouring group participation in the hydrolysis of acetylcholine

3.12                                                         3.12

For many uses (e.g. in dentistry) a quick acting, short duration muscle relaxant is required. Hence, it was important to design a compound that was not only selective but also readily deactivated. Atracurium benzenesulfonate 3.17 was developed from these studies. Not only is it easily hydrolysed but it also undergoes a rapid Hofmann elimination 3.18 to inactive products. This elimination is facilitated by the carbonyl group of the ester, which renders the adjacent hydrogens acidic. Despite its apparent complexity, it is made by a simple synthesis from pentane-1,5- diol 3.14, acryloyl chloride 3.15 and the alkaloid papaverine 3.16. It is worth noting the flexibility of this synthesis in terms of the analogues that might be prepared for structure:activity studies. In particular, the length of the spacer group between the two quaternary nitrogen atoms may be easily varied.

A number of local pain-killers and local anaesthetics have acetylcholine fragments. For example, suxamethonium chloride 3.19 is used in a number of throat lozenges.