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-].C53=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 iodide or HS-310) [1] is an aminosteroid neuromuscular-blocking drug that was investigated as a muscle relaxant for use in anesthesia. It acts as a competitive antagonist of the nicotinic acetylcholine receptor at the neuromuscular junction. [2] By blocking these receptors, it prevents acetylcholine from triggering muscle contraction, leading to muscle relaxation.

Contents

Medical use and discontinuation

Candocuronium was clinically evaluated in India for providing skeletal muscle relaxation during surgery, facilitating tracheal intubation, and assisting with mechanical ventilation. [3] According to Talukdar and Sarkar, it showed a rapid onset of action and a short duration in the body, but its development was halted due to cardiovascular side effects, particularly tachycardia. [3] Several studies suggested that the severity of these effects were similar to that of the clinically established neuromuscular blocker, pancuronium bromide. [4] [5] [6] [7] Candocuronium was also noted to have little to no ganglion-blocking activity and a greater potency than pancuronium. [1]

History and development

Rationale and design

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). [8] The design of candocuronium places it in a series of mono- and bis-quaternary azasteroids. The approach adopted in its development used the rigid steroid skeleton as a spacer to hold two quaternary ammonium groups (inspired by the alkaloid malouetine), which incorporate fragments resembling choline or acetylcholine, at a specific distance. [8]

Synthesis and early analogs

The research program first produced HS-342, a bis-quaternary agent that was reportedly equipotent with tubocurarine and had one-third its duration of action. However, it was deemed unsuitable for further clinical evaluation. [9] [10]

Subsequent chemical modifications of HS-342 led to the synthesis of two related derivatives: HS-310 (later named candocuronium) and HS-347. [1] [8] HS-347, though equipotent with tubocurarine, was precluded from clinical trials because it exhibited considerable ganglion-blocking activity, which potentially leads to undesirable autonomic side effects. [11] [12]

Further modifications and legacy

H-310 did not achieve the desired clinical profile, which led to the continued modification of its structure, ultimately resulting in the creation of dihydrochandonium (HS-626). The new variant was an analog and was reported to be a slightly improved neuromuscular blocking profile and no vagolytic effects. [13] [14] However, this benefit was not considered significant enough to advance the compound to human trials. [15]

The discovery of candocuronium prompted further research into modifications of the androstane nucleus, particularly at the 3- and 16-positions, leading to the development of other agents considered for clinical testing. [16] [17] [18] [19]

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". The Journal of Pharmacy and Pharmacology. 26 (11): 871–877. doi:10.1111/j.2042-7158.1974.tb09195.x. PMID   4156557. S2CID   37704229.
  2. ↑ Harvey AL, Paul D, Rodger IW, Singh H (Aug 1976). "Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations". The Journal of Pharmacy and Pharmacology. 28 (8): 617–619. doi:10.1111/j.2042-7158.1976.tb02812.x. PMID   11309. S2CID   7700031.
  3. 1 2 Talukdar A, Sarkar D (August 2023). "Catalyzing the Future of Medicinal Chemistry Research in India". Journal of Medicinal Chemistry. 66 (16): 10868–10877. doi:10.1021/acs.jmedchem.3c01304. PMID   37561395.
  4. ↑ Dasgupta D, Gupta KC, Vispute AV, Karandikar SM (Apr 1990). "Comparative clinical evaluation of chandonium iodide and pancuronium bromide as muscle relaxant". Journal of Postgraduate Medicine. 36 (2): 95–99. PMID   2151453.
  5. ↑ Dasgupta D, D'Souza M, Shah SJ, Gupta KC, Satoskar RS (Mar 1988). "Clinical evaluation of chandonium iodide as muscle relaxant". The Indian Journal of Medical Research. 87: 298–302. PMID   3397166.
  6. ↑ Kumar D, Bhatia VK, Yajnik S, Gaur SP, Nityanand S (Oct 1990). "Clinical evaluation of chandonium iodide as a nondepolarising muscle relaxant". The Indian Journal of Medical Research. 92: 367–370. PMID   2148735.
  7. ↑ 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.
  8. 1 2 3 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. 0 (12): 1475–1479. doi:10.1039/p19740001475. PMID   4472321.
  9. ↑ 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". The Journal of Pharmacy and Pharmacology. 25 (6): 441–446. doi:10.1111/j.2042-7158.1973.tb09130.x. PMID   4146581. S2CID   46013073.
  10. ↑ 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". European Journal of Pharmacology. 22 (2): 129–134. doi:10.1016/0014-2999(73)90002-2. PMID   4715215.
  11. ↑ 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". Clinical and Experimental Pharmacology & Physiology. 2 (2): 159–170. doi:10.1111/j.1440-1681.1975.tb01830.x. PMID   237641. S2CID   21840628.
  12. ↑ Teerapong P, Marshall IG, Harvey AL, Singh H, Paul D, Bhardwaj TR, et al. (Aug 1979). "The effects of dihydrochandonium and other chandonium analogues on neuromuscular and autonomic transmission". The Journal of Pharmacy and Pharmacology. 31 (8): 521–528. doi:10.1111/j.2042-7158.1979.tb13576.x. PMID   39992. S2CID   37032460.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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". The Journal of Pharmacy and Pharmacology. 33 (7): 451–457. doi:10.1111/j.2042-7158.1981.tb13831.x. PMID   6115032. S2CID   26115020.
  16. ↑ Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Feb 2001). "Synthesis and neuromuscular blocking activity of 16β-piperidinosteroidal derivatives". European Journal of Medicinal Chemistry. 36 (2): 195–202. doi:10.1016/s0223-5234(00)01205-8. PMID   11311750.
  17. ↑ Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Nov 2002). "Synthesis and neuromuscular blocking activity of 16β-N-methylpiperazino steroidal derivatives". European Journal of Medicinal Chemistry. 37 (11): 901–908. doi:10.1016/s0223-5234(02)01413-7. PMID   12446049.
  18. ↑ Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in rat". Indian Journal of Experimental Biology. 23 (5): 253–257. PMID   4077122.
  19. ↑ Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in monkey". Indian Journal of Experimental Biology. 23 (5): 258–261. PMID   4077123.
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