text: Curare is a crude extract from certain South American plants in the genera Strychnos and Chondrodendron, originally brought to Europe by explorers such as Walter Raleigh Edward Bancroft, a chemist and physician in the 16th century brought samples of crude curare from South America back to the Old-World. The effect of curare was experimented with by Sir Benjamin Brodie when he injected small animals with curare, and found that the animals stopped breathing but could be kept alive by inflating their lungs with bellows. This observation led to the conclusion that curare can paralyse the respiratory muscles. It was also experimented by Charles Waterton in 1814 when he injected three donkeys with curare. The first donkey was injected in the shoulder and died afterward. The second donkey had a tourniquet applied to the foreleg and was injected distal to the tourniquet. The donkey lived while the tourniquet was in place but died after it was removed. The third donkey after injected with curare appeared to be dead but was resuscitated using bellows. Charles Waterton's experiment confirmed the paralytic effect of curare.
  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 Chondrodendron 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.
  Neurologist Walter Freeman learned about curare and suggested to Richard Gill, a patient suffering from multiple sclerosis, that he try using it. Gill brought 25 pounds of raw curare from Ecuador. The raw curare was then given to Squibb and Sons to derive an effective antidote to curare. In 1942, Wintersteiner and Dutcher (two scientists working for Squibb and Sons) isolated the alkaloid d-tubocurarine. Soon after, they developed a preparation of curare called Intocostrin.
  At the same time in Montreal, Harold Randall Griffith and his resident Enid Johnson at the Homeopathic Hospital administered curare to a young patient undergoing appendectomy. This was the first use of NMBA as muscle relaxant in anesthesia.
  The 1940s, 1950s and 1960s saw the rapid development of several synthetic NMBA. Gallamine was the first synthetic NMBA used clinically. 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 drugs that had better pharmacological properties. Research on these molecules helped improve understanding of the physiology of neurons and receptors.