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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":[attribution needed] a non-depolarizing replacement for the most popular clinically used depolarizing agent, suxamethonium (succinylcholine).
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[how?] led to two other notable agents,[editorializing] 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.[editorializing]
However, candocuronium did not provide the desired profile,[clarification needed] and a further extension of research was undertaken to overcome its limitations.[clarification needed] This led to four more promising compounds,[editorializing] HS-692, HS-693, HS-704 and HS-705,[how?] whose onset and duration were indinguishable from candocuronium, but, unfortunately,[editorializing] all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. To improve on potency, further modifications of the candocuronium nucleus were undertaken,[clarification needed] leading to the identification of yet another promising compound,[editorializing] 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[peacock term][neutrality is disputed] has not yet yielded an agent worthy of expanded evaluation to clinical testing in this azasteroidal class of neuromuscular blocking agents.
^ abSingh H, Paul D (1974). "Steroids and related studies. XXV. Chandonium iodide (17a-methyl-3beta-pyrrolidino-17a-aza-D-homoandrost-5-ene dimethiodide) and other quaternary ammonium steroid analogues". J Chem Soc Perkin 112: 1475–1479. doi:10.1039/p19740001475. PMID4472321.
^Marshall IG, Paul D, Singh H (Jun 1973). "Some actions of 4,17a-dimethyl-4,17a-diaza-D-homo-5alpha-androstane dimethiodide (HS-342), a new neuromuscular blocking drug". J Pharm Pharmacol25 (6): 441–446. doi:10.1111/j.2042-7158.1973.tb09130.x. PMID4146581.
^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 Pharmacol22 (2): 129–134. doi:10.1016/0014-2999(73)90002-2. PMID4715215.
^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 Physiol2 (2): 159–170. doi:10.1111/j.1440-1681.1975.tb01830.x. PMID237641.
^ abTeerapong P, Marshall IG, Harvey AL, Singh H, Paul D, Bhardwaj TR, Ahuja NK (Aug 1979). "The effects of dihydrochandonium and other chandonium analogues on neuromuscular and autonomic transmission". J Pharm Pharmacol31 (8): 521–528. doi:10.1111/j.2042-7158.1979.tb13576.x. PMID39992.
^Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in rat". Indian J Exp Biol23 (5): 253–257. PMID4077122.
^Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in monkey". Indian J Exp Biol23 (5): 258–261. PMID4077123.
^Singh H, Bhardwaj TR, Ahuja NK, Paul D (1979). J Chem Soc, Perk Trans I: 305.
^Singh H, Bhardwaj TR, Paul D (1979). J Chem Soc, Perk Trans I: 2451.
^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 Pharmacol33 (7): 451–457. doi:10.1111/j.2042-7158.1981.tb13831.x. PMID6115032.
^Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Feb 2001). "Synthesis and neuromuscular blocking activity of 16β-piperidinosteroidal derivatives". Eur J Med Chem36 (2): 195–202. doi:10.1016/s0223-5234(00)01205-8. PMID11311750.
^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 Chem37 (11): 901–908. doi:10.1016/s0223-5234(02)01413-7. PMID12446049.