Neuromuscular-blocking Drug - History

History

Curare is a crude extract from certain South American plants in the genera Strychnos and Chondodendron, originally brought to Europe by explorers such as Walter Raleigh It was known in the 19th century to have a paralysing effect, due in part to the studies of scientists like Claude Bernard. D-tubocurarine a mono-quaternary alkaloid was isolated from Chondodendron tomentosum in 1942, and it was shown to be the major constituent in curare responsible for producing the paralysing effect. At that time, it was known that curare and, therefore, d-tubocurarine worked at the neuromuscular junction. The isolation of tubocurarine and its marketing as the drug Intocostrin led to more research in the field of neuromuscular-blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance between the two quaternary ammonium heads.

Further research led to the development of synthesized molecules with different curariform effects, depending on the distance between the quaternary ammonium groups. One of the synthesized bis-quaternaries was decamethonium a 10-carbon bis-quaternary compound. Following research with decamethonium, scientists developed suxamethonium, which is a double acetylcholine molecule that was connected at the acetyl end. The discovery and development of suxamethonium lead to a Nobel Prize in medicine in 1957. Suxamethonium showed different blocking effect in that its effect was achieved more quickly and augmented a response in the muscle before block. Also, tubocurarine effects were known to be reversible by acetylcholinesterase inhibitors, whereas decamethonium and suxamethonium block were not reversible.

Another compound malouétine that was a bis-quaternary steroid was isolated from the plant Malouetia bequaertiana and showed curariform activity. This led to the synthetic drug pancuronium a bis-quaternary steroid and subsequently other chemicals that had better pharmacological properties as drugs.

These molecules discussed above and research devoted to them led to many other compounds with different pharmacological properties and research in drug development as well as they helped to better the understanding the physiology of neurons and receptors.