Candocuronium iodide

Last updated
Candocuronium iodide
Candocuronium iodide.png
Clinical data
Other namesChandonium iodide; HS-310
Pregnancy
category
  • Not applicable
Routes of
administration 		IV
ATC code
  • none
Legal status
Legal status
  • Discontinued from clinical development
Pharmacokinetic data
Bioavailability 100% (IV)[ citation needed ]
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H46I2N2
Molar mass 640.477 g·mol−1
3D model (JSmol)
  • [I-].[I-].C\53=C/C[C@@H]1[C@H](CC[C@]2([C@H]1CCC[N+]2(C)C)C)[C@@]3(C)CC[C@H]([N+]4(C)CCCC4)C/5
  • InChI=1S/C26H46N2.2HI/c1-25-14-12-21(28(5)17-6-7-18-28)19-20(25)10-11-22-23(25)13-15-26(2)24(22)9-8-16-27(26,3)4;;/h10,21-24H,6-9,11-19H2,1-5H3;2*1H/q+2;;/p-2/t21-,22+,23-,24-,25-,26-;;/m0../s1 X mark.svgN
  • Key:GGAGIPMNQXAXNH-XDMKMBKMSA-L X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Candocuronium iodide (INN, formerly chandonium, HS-310) [1] 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 that was about the same as the clinically established pancuronium bromide. [2] [3] [4] [5] Candocuronium demonstrated a short duration in the body, but a rapid onset of action. It had little to no Ganglion blocking activity, with a greater potency than pancuronium. [1]

Contents

Background

As with other neuromuscular-blocking agents, candocuronium is a preferential competitive antagonist of nicotinic acetylcholine receptors. [6] The agent was developed by the laboratory of Harkishan Singh, Panjab University, Chandigarh, India, as part of the search for a non-depolarizing replacement for the most popular clinical depolarizing agent, suxamethonium (succinylcholine).[ citation needed ]

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 [7] 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. [8] [9] 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). [1] [7] HS-347 was equipotent with tubocurarine but exhibited considerable ganglion blocking activity, and therefore the drug proceeded to clinical trials. [10] [11] [12] [13]

Modifications to the candocuronium design

Candocuronium did not provide the desired profile that was required to fulfill its purpose (to be used as an neuromuscular-blocking anesthetic) and a further extension of research was undertaken to overcome its limitations in that regard. Further research provided derivatives of the candocuronium design, HS-692, HS-693, HS-704 and HS-705, [14] whose onset and duration were indistinguishable from candocuronium, but all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. [11] To improve on potency, further research was conducted on derivatives of the candocuronium nucleus, leading to the identification of yet another potentially useful compound, HS-626. [15] Upon further preclinical evaluation, [16] 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 undesirable cardiovascular effects. The Marshall group then explored other modifications at the 3- and 16-positions of the androstane nucleus, [17] [18] and yielded an agent that can go through expanded evaluation to clinical testing.

References

  1. 1 2 3 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 Pharmacol. 26 (11): 871–877. doi:10.1111/j.2042-7158.1974.tb09195.x. PMID   4156557. S2CID   37704229.
  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. doi:10.1111/j.2042-7158.1976.tb02812.x. PMID   11309. S2CID   7700031.
  7. 1 2 Singh H, Paul D (1974). "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 of the Chemical Society, Perkin Transactions 1. 12 (12): 1475–1479. doi:10.1039/p19740001475. 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. doi:10.1111/j.2042-7158.1973.tb09130.x. PMID   4146581. S2CID   46013073.
  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. doi:10.1016/0014-2999(73)90002-2. 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. doi:10.1111/j.1440-1681.1975.tb01830.x. PMID   237641. S2CID   21840628.
  11. 1 2 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. doi:10.1111/j.2042-7158.1979.tb13576.x. PMID   39992. S2CID   37032460.
  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). "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 of the Chemical Society, Perkin Transactions 1: 305–307. doi:10.1039/P19790000305.
  15. ↑ Singh H, Bhardwaj TR, Paul D (1979). "Steroids and related studies. Part 48. A chandonium iodide analogue possessing an acetylcholine-like moiety". Journal of the Chemical Society, Perkin Transactions 1: 2451. doi:10.1039/p19790002451.
  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. doi:10.1111/j.2042-7158.1981.tb13831.x. PMID   6115032. S2CID   26115020.
  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. doi:10.1016/s0223-5234(00)01205-8. 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. doi:10.1016/s0223-5234(02)01413-7. PMID   12446049.
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