Candocuronium iodide (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

, formerly chandonium, HS-310) is an

aminosteroid Aminosteroids are a group of steroids with a similar structure based on an amino- substituted steroid nucleus. They are neuromuscular blocking agents, acting as competitive antagonists of the nicotinic acetylcholine receptor (nAChR), and block t ...

neuromuscular-blocking drug Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcho ...

. It was clinically evaluated in

India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...

for use in

anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...

for

endotracheal intubation Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs. It is frequently ...

, and for providing

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

relaxation and assistance

mechanical ventilation Mechanical ventilation or assisted ventilation is the Medicine, medical term for using a ventilator, ventilator machine to fully or partially provide artificial ventilation. Mechanical ventilation helps move air into and out of the lungs, wit ...

during surgery. Its development was discontinued due to cardiovascular side effects, primarily

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

, the severity of which is similar to the clinically established

pancuronium bromide Pancuronium (trademarked as Pavulon) is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States. Mech ...

. Candocuronium has a short duration in the body, but a rapid onset of action, with little to no ganglion-blocking activity and greater potency than

Background

Candocuronium iodide, like other neuromuscular-blocking agents, is a preferential competitive antagonist of nicotinic acetylcholine receptors. It was developed by the laboratory of

Harkishan Singh Harkishan Singh (25 November 1928 – 20 March 2020) was a professor in pharmaceutical chemistry at Panjab University (Chandigarh, India). He was a pharmaceutical academic, medicinal chemistry researcher, and science historian. Singh researc ...

Panjab University Panjab University (PU) is an Indian collegiate public state university located in Chandigarh. Funded through both State and Union governments, it is considered a state university. It traces its origins to the University of the Punjab in Lahor ...

in search of a non-depolarizing replacement for the popular clinical depolarizing agent

suxamethonium Suxamethonium chloride (brand names Scoline and Sucostrin, among others), also known as suxamethonium or succinylcholine, or simply sux in medical abbreviation, is a medication used to cause short-term paralysis as part of general anesthesia. T ...

(

succinylcholine Suxamethonium chloride (brand names Scoline and Sucostrin, among others), also known as suxamethonium or succinylcholine, or simply sux in medical abbreviation, is a medication used to cause short-term paralysis as part of general anesthesia. T ...

Design

The ''mono''- and ''bis''-quaternary azasteroid series of compounds, to which Candocuronium iodide belongs, are based on the use of the steroid skeleton to provide a somewhat rigid distance between the two quaternary ammonium centers, with appendages incorporating fragments of choline or acetylcholine. The discovery program initiated by Singh initially led to the synthesis of the ''bis''-quaternary non-depolarizing agent HS-342 (4,17a-dimethyl-4,17a-diaza-D-homo-5α-androstane methiodide), which was equipotent with tubocurarine and one-third its duration of action, however, was not found suitable for further clinical evaluation. Modifications of the chemical structure of HS-342 led to the synthesis of two related derivatives, HS-347 and HS-310 (later named chandonium and candocuronium, respectively). HS-347 was equipotent with tubocurarine but exhibited considerable ganglion blocking activity, precluding it from advancing to clinical trials.

Modifications to the candocuronium design

Candocuronium did not provide the profile required to fulfill its purpose as a neuromuscular-blocking anesthetic. Further research provided derivatives of the candocuronium design—HS-692, HS-693, HS-704, and HS-705—whose onset and duration were indistinguishable from candocuronium, but all demonstrated vagolytic effects and much weaker potencies than candocuronium. To improve potency, further research was conducted on derivatives of the candocuronium nucleus, leading to the identification of HS-626. Upon further preclinical evaluation, while HS-626 showed a slightly improved way of blocking neuromuscular activity compared to candocuronium, the benefit wasn't significant enough to move it to human trials.

Modifications at 3- and 16-positions of androstane nucleus

The discovery of candocuronium led to numerous related neuromuscular-blocking agents with short durations of action, but also undesirable cardiovascular effects. Further research explored other modifications at the 3- and 16-positions of the androstane nucleus, yielding an agent suitable for expanded evaluation to clinical testing.

References

External links

* {{DEFAULTSORT:Candocuronium Iodide Muscle relaxants Nicotinic antagonists Quaternary ammonium compounds Iodides Pyrrolidines Neuromuscular blockers