|Synonyms||Chandonium iodide; HS-310|
|Chemical and physical data|
|Molar mass||640.47 g/mol|
|3D model (Jmol)||Interactive image|
|(what is this?)|
Candocuronium iodide (INN, formerly chandonium, HS-310) is the prototypical azasteroidal neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs. Its potential adjunctive use in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India, but further development was discontinued because of attendant undesirable cardiovasular effects, primarily tachycardia that was no worse than but also not an improvement over the clinically established pancuronium bromide. Candocuronium demonstrated a short duration and a rapid onset of action, with little or no ganglion blocking activity, and it was only slightly less potent than pancuronium.
As with other established neuromuscular blocking agents, candocuronium preferentially antagonizes competitively the nicotinic subtype of acetylcholine receptors. The agent was developed by the laboratory of Harkishan Singh, Panjab University, Chandigarh, India, as part of the search for "the Holy Grail of neuromuscular blocking agents": a non-depolarizing replacement for the most popular clinically used 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: 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) that was equipotent with tubocurarine and with one-third its duration of action, but not suitable for further clinical evaluation. Modifications of the HS-342 structure led to two other notable agents, HS-347 and HS-310 (subsequently named chandonium, then candocuronium). HS-347 was equipotent with tubocurarine but exhibited considerable ganglion blocking activity; candocuronium appeared to be suitably placed for clinical trials following encouraging preclinical evaluations.
Modifications to the candocuronium design
However, candocuronium did not provide the desired profile, and a further extension of research was undertaken to overcome its limitations. This led to four more promising compounds, HS-692, HS-693, HS-704 and HS-705, whose onset and duration were indinguishable from candocuronium, but, unfortunately, all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. To improve on potency, further modifications of the candocuronium nucleus were undertaken, leading to the identification of yet another promising compound, HS-626. Unfortunately, upon further preclinical evaluation in the cat and isolated preparations, HS-626 demonstrated a slightly more desirable neuromuscular blocking profile than that of 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 having attendant undesirable cardiovascular effects. The Marshall group then explored other modifications at the 3- and 16-positions of the androstane nucleus, but the admirable undaunted persistence has not yet yielded an agent worthy of expanded evaluation to clinical testing in this azasteroidal class of neuromuscular blocking agents.
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- Suri YV (1984). Chandonium-iodide. New non-depolarising muscle relaxant. In: "Anaesthesiology. Clinical Pharmacology" Suri YV, Singh D (Eds.) New Delhi: Vani Educational Books; 28-35.
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- Marshall IG, Paul D, Singh H (May 1973). "The neuromuscular and other blocking actions of 4,17a-dimethyl-4,17a-diaza-d-homo-5 -androstane dimethiodide (HS-342) in the anaesthetized cat". Eur J Pharmacol. 22 (2): 129–134. doi:10.1016/0014-2999(73)90002-2. PMID 4715215.
- Gandiha A, Marshall IG, Paul D, Rodger IW, Scott W, Singh H (Mar–Apr 1975). "Some actions of chandonium iodide, a new short-acting muscle relaxant, in anaesthetized cats and on isolated muscle preparations". Clin Exp Pharmacol Physiol. 2 (2): 159–170. doi:10.1111/j.1440-1681.1975.tb01830.x. PMID 237641.
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- Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in monkey". Indian J Exp Biol. 23 (5): 258–261. PMID 4077123.
- Singh H, Bhardwaj TR, Ahuja NK, Paul D (1979). J Chem Soc, Perk Trans I: 305. Missing or empty
- Singh H, Bhardwaj TR, Paul D (1979). J Chem Soc, Perk Trans I: 2451. Missing or empty
- Marshall IG, Harvey AL, Singh H, Bhardwaj TR, Paul D (Jul 1981). "The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments". J Pharm Pharmacol. 33 (7): 451–457. doi:10.1111/j.2042-7158.1981.tb13831.x. PMID 6115032.
- Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Feb 2001). "Synthesis and neuromuscular blocking activity of 16β-piperidinosteroidal derivatives". Eur J Med Chem. 36 (2): 195–202. doi:10.1016/s0223-5234(00)01205-8. PMID 11311750.
- Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Nov 2002). "Synthesis and neuromuscular blocking activity of 16β-N-methylpiperazino steroidal derivatives". Eur J Med Chem. 37 (11): 901–908. doi:10.1016/s0223-5234(02)01413-7. PMID 12446049.
- Neuromuscular blocking agents at the US National Library of Medicine Medical Subject Headings (MeSH)