The history of Atracurium besylate

Atracurium besylate was first synthesized in 1974 by George H. Dewar,[2] a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlake's medicinal chemistry research group in the Department of Pharmacy at the Strathclyde University, Scotland. Dewar first named this compound "33A74"[2] before its eventual emergence as atracurium. Atracurium was the culmination of a rational approach to drug design to produce the first non-depolarizing non-steroidal skeletal muscle relaxant that undergoes chemodegradation in vivo. The term chemodegradation was coined by Roger D. Waigh, PhD,[3] also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University to The Wellcome Foundation Ltd. UK, which developed the drug (then known as BW 33A[4]) and its introduction to first human trials in 1979,[5][6] and then eventually to its first introduction (as a mixture of all ten stereoisomers[7]) into clinical anesthetic practice in the UK, in 1983, under the tradename of Tracrium.
The premise to the design of atracurium and several of its congeners stemmed from the knowledge that a bis-quaternary structure is essential for neuromuscular blocking activity: ideally, therefore, a chemical entity devoid of this bis-quaternary structure via susceptibility to inactive breakdown products by enzymic-independent processes would prove to be invaluable in the clinical use of a drug with a predictable onset and duration of action. Hofmann elimination provided precisely this basis: it is a chemical process in which a suitably activated quaternary ammonium compound can be degraded by the mildly alkaline conditions present at physiological pH and temperature.[8] In effect, Hofmann elimination is a retro-Michael addition chemical process. It is important to note here that the physiological process of Hofmann elimination differs from the non-physiological Hofmann degradation process: the latter is a chemical reaction in which a quaternary ammonium hydoxide solid salt is heated to 100 °C, or an aqueous solution of the salt is boiled. Regardless of which Hofmann process is referenced, the end-products in both situations will be the same: an alkene and a tertiary amine.