# Candocuronium iodide

Candocuronium iodide (INN, formerly chandonium, HS-310) is an aminosteroid neuromuscular-blocking drug. It was clinically evaluated in India for use within anesthesia for endotracheal intubation and for providing skeletal muscle relaxation during surgery or mechanical ventilation. Its development was discontinued due to cardiovascular effects, primarily tachycardia, which was approximately the same as that seen with the clinically established pancuronium bromide. Candocuronium had a short duration in the body, but a rapid onset of action, and little to no Ganglion blocking activity, with a greater potency than pancuronium.

## Background

Candocuronium, like other neuromuscular-blocking agents, is a preferential competitive antagonist of nicotinic acetylcholine receptors. It was developed by the laboratory of Harkishan Singh at Panjab University as part of a search for a non-depolarizing replacement for the popular clinical depolarizing agent, suxamethonium (succinylcholine).

## Design of candocuronium

The mono- and bis-quaternary azasteroid series of compounds, to which candocuronium belongs, are based on the same principle that led to aminosteroids such as pancuronium, vecuronium and rocuronium: 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 dimethiodide), which was equipotent with tubocurarine and had one-third its duration of action, but was not 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 (subsequently named chandonium, then candocuronium). 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, and research was extended to overcome its limitations. 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, HS-626 demonstrated a slightly more desirable neuromuscular-blocking profile than candocuronium, but its overall improvement was insufficient to warrant advancement to clinical testing.

## 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. The Marshall group then explored other modifications at the 3- and 16-positions of the androstane nucleus, yielding an agent suitable for expanded evaluation to clinical testing.