candocuronium iodide

Candocuronium was clinically evaluated in India for providing skeletal muscle relaxation during surgery, facilitating tracheal intubation, and assisting with mechanical ventilation. While it showed a rapid onset of action and a short duration in the body, its development was halted due to cardiovascular side effects, particularly tachycardia. Several studies suggested, however, that the severity of these effects was similar to that of the clinically established neuromuscular blocker pancuronium bromide.{{cite journal | vauthors = Dasgupta D, Gupta KC, Vispute AV, Karandikar SM | title = Comparative clinical evaluation of chandonium iodide and pancuronium bromide as muscle relaxant | journal = Journal of Postgraduate Medicine | volume = 36 | issue = 2 | pages = 95–99 | date = Apr 1990 | pmid = 2151453 }}{{cite journal | vauthors = Dasgupta D, D'Souza M, Shah SJ, Gupta KC, Satoskar RS | title = Clinical evaluation of chandonium iodide as muscle relaxant | journal = The Indian Journal of Medical Research | volume = 87 | pages = 298–302 | date = Mar 1988 | pmid = 3397166 }}{{cite journal | vauthors = Kumar D, Bhatia VK, Yajnik S, Gaur SP, Nityanand S | title = Clinical evaluation of chandonium iodide as a nondepolarising muscle relaxant | journal = The Indian Journal of Medical Research | volume = 92 | pages = 367–370 | date = Oct 1990 | pmid = 2148735 }}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. Candocuronium was also noted to have little to no ganglion-blocking activity and greater potency than pancuronium.

Candocuronium iodide is a preferential competitive antagonist of nicotinic acetylcholine receptors at the neuromuscular junction.{{cite journal | vauthors = Harvey AL, Paul D, Rodger IW, Singh H | title = Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations | journal = The Journal of Pharmacy and Pharmacology | volume = 28 | issue = 8 | pages = 617–619 | date = Aug 1976 | pmid = 11309 | doi = 10.1111/j.2042-7158.1976.tb02812.x | s2cid = 7700031 }} By blocking these receptors, it prevents acetylcholine from triggering muscle contraction, leading to muscle relaxation.

The drug was developed in the laboratory of Harkishan Singh at Panjab University as part of a research program seeking a non-depolarizing neuromuscular blocker to replace the widely used depolarizing agent suxamethonium (succinylcholine).{{cite journal | vauthors = Singh H, Paul D | title = Steroids and related studies. Part XXV. Chandonium iodide (17a-methyl-3β-pyrrolidino-17a-aza-D-homoandrost-5-ene dimethiodide) and other quaternary ammonium steroid analogues | journal = Journal of the Chemical Society, Perkin Transactions 1 | volume = 0 | issue = 12 | pages = 1475–1479 | year = 1974 | pmid = 4472321 | doi = 10.1039/p19740001475 }} The design of candocuronium belongs to a series of mono- and bis-quaternary azasteroids. This approach used the rigid steroid skeleton as a spacer to hold two quaternary ammonium groups, which incorporate fragments resembling choline or acetylcholine, at a specific distance.

The research program first produced HS-342, a bis-quaternary agent that was equipotent with tubocurarine and had one-third its duration of action. However, it was deemed unsuitable for further clinical evaluation.{{cite journal | vauthors = Marshall IG, Paul D, Singh H | title = Some actions of 4,17a-dimethyl-4,17a-diaza-D-homo-5alpha-androstane dimethiodide (HS-342), a new neuromuscular blocking drug | journal = The Journal of Pharmacy and Pharmacology | volume = 25 | issue = 6 | pages = 441–446 | date = Jun 1973 | pmid = 4146581 | doi = 10.1111/j.2042-7158.1973.tb09130.x | s2cid = 46013073 }}{{cite journal | vauthors = Marshall IG, Paul D, Singh H | title = The neuromuscular and other blocking actions of 4,17a-dimethyl-4,17a-diaza-d-homo-5 -androstane dimethiodide (HS-342) in the anaesthetized cat | journal = European Journal of Pharmacology | volume = 22 | issue = 2 | pages = 129–134 | date = May 1973 | pmid = 4715215 | doi = 10.1016/0014-2999(73)90002-2 }}

Subsequent chemical modifications of HS-342 led to the synthesis of two related derivatives: HS-310 (later named candocuronium) and HS-347. HS-347, though equipotent with tubocurarine, was precluded from clinical trials because it exhibited considerable ganglion-blocking activity, which can lead to undesirable autonomic side effects.{{cite journal | vauthors = Gandiha A, Marshall IG, Paul D, Rodger IW, Scott W, Singh H | title = Some actions of chandonium iodide, a new short-acting muscle relaxant, in anaesthetized cats and on isolated muscle preparations | journal = Clinical and Experimental Pharmacology & Physiology | volume = 2 | issue = 2 | pages = 159–170 | date = Mar–Apr 1975 | pmid = 237641 | doi = 10.1111/j.1440-1681.1975.tb01830.x | s2cid = 21840628 }}{{cite journal | vauthors = Teerapong P, Marshall IG, Harvey AL, Singh H, Paul D, Bhardwaj TR, Ahuja NK | title = The effects of dihydrochandonium and other chandonium analogues on neuromuscular and autonomic transmission | journal = The Journal of Pharmacy and Pharmacology | volume = 31 | issue = 8 | pages = 521–528 | date = Aug 1979 | pmid = 39992 | doi = 10.1111/j.2042-7158.1979.tb13576.x | s2cid = 37032460 }}

Although candocuronium itself did not achieve the desired clinical profile, researchers continued to modify its structure. These efforts led to the creation of dihydrochandonium (HS-626), an analog with a slightly improved neuromuscular blocking profile and no vagolytic effects.{{cite journal | vauthors = Singh H, Bhardwaj TR, Ahuja NK, Paul D | title = Steroids and related studies. Part 44. 17a-Methyl-3β-(N-pyrrolidinyl)17a-aza-D-homo-5α-androstane bis(methiodide)(dihydrochandonium iodide) and certain other analogues of chandonium iodide | journal = Journal of the Chemical Society, Perkin Transactions 1 | pages = 305–307 | year = 1979 | doi = 10.1039/P19790000305 }}{{cite journal | vauthors = Singh H, Bhardwaj TR, Paul D | title = Steroids and related studies. Part 48. A chandonium iodide analogue possessing an acetylcholine-like moiety | journal = Journal of the Chemical Society, Perkin Transactions 1 | pages = 2451 | year = 1979 | doi = 10.1039/p19790002451 }} However, this benefit was not considered significant enough to advance the compound to human trials.{{cite journal | vauthors = Marshall IG, Harvey AL, Singh H, Bhardwaj TR, Paul D | title = The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments | journal = The Journal of Pharmacy and Pharmacology | volume = 33 | issue = 7 | pages = 451–457 | date = Jul 1981 | pmid = 6115032 | doi = 10.1111/j.2042-7158.1981.tb13831.x | s2cid = 26115020 }}

The discovery of candocuronium spurred further research into other modifications of the androstane nucleus, particularly at the 3- and 16-positions, ultimately yielding other agents that were considered for clinical testing.{{cite journal | vauthors = Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG | title = Synthesis and neuromuscular blocking activity of 16β-piperidinosteroidal derivatives | journal = European Journal of Medicinal Chemistry | volume = 36 | issue = 2 | pages = 195–202 | date = Feb 2001 | pmid = 11311750 | doi = 10.1016/s0223-5234(00)01205-8 }}{{cite journal | vauthors = Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG | title = Synthesis and neuromuscular blocking activity of 16β-N-methylpiperazino steroidal derivatives | journal = European Journal of Medicinal Chemistry | volume = 37 | issue = 11 | pages = 901–908 | date = Nov 2002 | pmid = 12446049 | doi = 10.1016/s0223-5234(02)01413-7 }}{{cite journal | vauthors = Singh H, Chaudhary AK | title = Pharmacokinetics and disposition of chandonium iodide in rat | journal = Indian Journal of Experimental Biology | volume = 23 | issue = 5 | pages = 253–257 | date = May 1985 | pmid = 4077122 }}{{cite journal | vauthors = Singh H, Chaudhary AK | title = Pharmacokinetics and disposition of chandonium iodide in monkey | journal = Indian Journal of Experimental Biology | volume = 23 | issue = 5 | pages = 258–261 | date = May 1985 | pmid = 4077123 }}

{{Reflist}}

• {{MeshName|Neuromuscular+blocking+agents}}

{{Muscle relaxants}}

{{Nicotinic acetylcholine receptor modulators}}

{{DEFAULTSORT:Candocuronium Iodide}}

Category:Muscle relaxants

Category:Nicotinic antagonists

Category:Quaternary ammonium compounds

Category:Iodides

Category:Pyrrolidines

Category:Neuromuscular blockers