Candocuronium iodide

Candocuronium iodide

Systematic (IUPAC) name
(4aS,4bR,8S,10aR,10bS,12aS)-1,1,10a,12a-tetramethyl-8-(1-methylpyrrolidin-1-ium-1-yl)-3,4,4a,4b,5,7,8,9,10,10b,11,12-dodecahydro-2H-naphtho[2,1-f]quinolin-1-ium diiodide
Clinical data
Pregnancy cat.	not applicable
Legal status	discontinued from clinical development
Routes	IV
Pharmacokinetic data
Bioavailability	100% (IV)
Identifiers
CAS number	54278-85-2 Y
ATC code	?
PubChem	CID 71537
UNII	SC80GNP08C N
Synonyms	Chandonium iodide; HS-310
Chemical data
Formula	C26H46I2N2
Mol. mass	640.47 g/mol
SMILES	eMolecules & PubChem
N(what is this?)  (verify)

Candocuronium iodide (formerly recognized as chandonium or HS-310^[1]) 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.^[2][3][4][5] Chandonium 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 bromide.^[1]

As noted with other well established neuromuscular blocking agents, chandonium preferentially antagonizes competitively the nicotinic subtype of acetycholine receptors.^[6] The agent was developed by researchers in the laboratories of Harkishan Singh at the Panjab University in Chandigarh, India, as part of the ongoing search for the Holy Grail of neuromuscular blocking agents: a non-depolarizing replacement for the most popular clinically used depolarizing agent, succinylcholine (suxamethonium).

The mono- and bis-quaternary azasteroid series of compounds (to which chandonium belongs) stems from the same principle that led to the invention of aminosteroids such as pancuronium, vecuronium and rocuronium: the use of the steroid skeleton to provide a somewhat rigid distance between the two quaternary ammoniumm centers with appendages incorporating fragments of choline or acetylcholine. The discovery program, initiated by Singh,^[7] initially led to the synthesis of a bis-quaternary non-depolarizing agent labelled 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.^[8][9]

Modifications around the structure of HS-342 led to two other notable agents, HS-347 and HS-310 (subsequently named chandonium).^[1][7] HS-347 was equipotent with tubocurarine but also exhibited considerable ganglion blocking activity, whereas chandonium appeared to be suitably placed for clinical trials following encouraging preclinical evaluations.^{[10][11][12][13]}

As already noted, chandonium still did not provide the desirable profile and a further extension of research was undertaken to overcome the limitations of chandonium. This led to four more promising compounds, HS-692, HS-693, HS-704 and HS-705.^[14] The onset and duration of these four agents were indinguishable from those of chandonium, but, unfortunately, all demonstrated profound vagolytic effects and much weaker potencies than those of chandonium.^[11] To improve on the potency, further modifications of the chandonium nucleus were undertaken, leading to the identification of yet another promising compound, HS-626.^[15] Unfortunately, upon further preclinical evaluations in the cat and isolated preparations,^[16] it was clearly evident that, although HS-626 demonstrated a slightly more desirable neuromuscular blocking profile than that of chandonium, the overall degree of improvement was insufficient to warrant advancement to clinical testing.

Overall, Singh's research group discovered and identified chandonium which spawned numerous related neuromuscular blocking agents with short durations of action but also attendant with undesirable cardiovascular effects. Subsequent further attempts to attain the intended goal led the group to explore other modifications at the 3 and 16 positions of the androstane nucleus,^[17][18] 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.

References

1. ^ ^{a b c} Gandiha A, Marshall IG, Paul D, Singh H (Nov 1974). "Neuromuscular and other blocking actions of a new series of mono and bisquaternary aza steroids". J Pharm Phamacol 26 (11): 871–877. PMID 4156557. 
2. ^ Dasgupta D, Gupta KC, Vispute AV, Karandikar SM (Apr 1990). "Comparative clinical evaluation of chandonium iodide and pancuronium bromide as muscle relaxant". J Postgrad Med 36 (2): 95–99. PMID 2151453. 
3. ^ Dasgupta D, D'Souza M, Shah SJ, Gupta KC, Satoskar RS (Mar 1988). "Clinical evaluation of chandonium iodide as muscle relaxant". Indian J Med Res 87: 298–302. PMID 3397166. 
4. ^ Kumar D, Bhatia VK, Yajnik S, Gaur SP, Nityanand S (Oct 1990). "Clinical evaluation of chandonium iodide as a nondepolarising muscle relaxant". Indian J Med Res 92: 367–370. PMID 2148735. 
5. ^ 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.
6. ^ Harvey AL, Paul D, Rodger IW, Singh H (1976). "Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations". J Pharm Pharmacol 28 (8): 617–619. PMID 11309. 
7. ^ ^{a b} Singh 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 1 12: 1475–1479. PMID 4472321. 
8. ^ 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 Pharmacol 25 (6): 441–446. PMID 4146581. 
9. ^ 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. PMID 4715215. 
10. ^ 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. PMID 237641. 
11. ^ ^{a b} Teerapong 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 Pharmacol 31 (8): 521–528. PMID 39992. 
12. ^ Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in rat". Indian J Exp Biol 23 (5): 253–257. PMID 4077122. 
13. ^ Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in monkey". Indian J Exp Biol 23 (5): 258–261. PMID 4077123. 
14. ^ Singh H, Bhardwaj TR, Ahuja NK, Paul D (1979). J Chem Soc, Perk Trans I: 305. 
15. ^ Singh H, Bhardwaj TR, Paul D (1979). J Chem Soc, Perk Trans I: 2451. 
16. ^ 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. PMID 6115032. 
17. ^ 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. PMID 11311750. 
18. ^ 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. PMID 12446049. 

External links

• MeSH Neuromuscular+blocking+agents