Candocuronium iodide explained

Candocuronium iodide (INN, formerly chandonium, HS-310)[1] is a aminosteroid neuromuscular-blocking drug. Its use within anesthesia for endotracheal intubation and for providing skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India, though further development was discontinued due to attendant 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]

Background

As with other neuromuscular-blocking agents, candocuronium preferentially antagonizes competitively the nicotinic subtype of 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).

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 HS-342 structure led to two other notable agents, HS-347 and HS-310 (subsequently named chandonium, then candocuronium).[1] [7] 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.[10] [11] [12] [13]

Modifications to the candocuronium design

Candocuronium did not provide the desired profile, and a further extension of research was undertaken to overcome its limitations. This led to four more potentially useful compounds, HS-692, HS-693, HS-704 and HS-705,[14] whose onset and duration were indinguishable from candocuronium, but all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. To improve on potency, further modifications of the candocuronium nucleus were undertaken, 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 attendant 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.

Notes and References

  1. Gandiha A, Marshall IG, Paul D, Singh H . Neuromuscular and other blocking actions of a new series of mono and bisquaternary aza steroids . J Pharm Pharmacol . Nov 1974 . 26 . 11 . 871–877 . 4156557 . 10.1111/j.2042-7158.1974.tb09195.x. 37704229 .
  2. Dasgupta D, Gupta KC, Vispute AV, Karandikar SM . Comparative clinical evaluation of chandonium iodide and pancuronium bromide as muscle relaxant . J Postgrad Med . Apr 1990. 36 . 2 . 95–99 . 2151453 .
  3. Dasgupta D, D'Souza M, Shah SJ, Gupta KC, Satoskar RS . Clinical evaluation of chandonium iodide as muscle relaxant . Indian J Med Res . Mar 1988. 87 . 298–302 . 3397166 .
  4. Kumar D, Bhatia VK, Yajnik S, Gaur SP, Nityanand S . Clinical evaluation of chandonium iodide as a nondepolarising muscle relaxant . Indian J Med Res . Oct 1990. 92 . 367–370 . 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 . Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations . J Pharm Pharmacol . 1976. 28 . 8 . 617–619 . 11309 . 10.1111/j.2042-7158.1976.tb02812.x. 7700031 .
  7. Singh H, Paul D . 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. 1974. 12 . 12. 1475–1479 . 4472321 . 10.1039/p19740001475.
  8. Marshall IG, Paul D, Singh H . Some actions of 4,17a-dimethyl-4,17a-diaza-D-homo-5alpha-androstane dimethiodide (HS-342), a new neuromuscular blocking drug . J Pharm Pharmacol . Jun 1973. 25 . 6 . 441–446 . 4146581 . 10.1111/j.2042-7158.1973.tb09130.x. 46013073 .
  9. Marshall IG, Paul D, Singh H . 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 . May 1973. 22 . 2 . 129–134 . 4715215 . 10.1016/0014-2999(73)90002-2.
  10. Gandiha A, Marshall IG, Paul D, Rodger IW, Scott W, Singh H . Some actions of chandonium iodide, a new short-acting muscle relaxant, in anaesthetized cats and on isolated muscle preparations . Clin Exp Pharmacol Physiol . Mar–Apr 1975 . 2 . 2 . 159–170 . 237641 . 10.1111/j.1440-1681.1975.tb01830.x. 21840628 .
  11. Teerapong P, Marshall IG, Harvey AL, Singh H, Paul D, Bhardwaj TR, Ahuja NK . The effects of dihydrochandonium and other chandonium analogues on neuromuscular and autonomic transmission . J Pharm Pharmacol . Aug 1979. 31 . 8 . 521–528 . 39992 . 10.1111/j.2042-7158.1979.tb13576.x. 37032460 .
  12. Singh H, Chaudhary AK . Pharmacokinetics and disposition of chandonium iodide in rat . Indian J Exp Biol . May 1985 . 23 . 5 . 253–257 . 4077122 .
  13. Singh H, Chaudhary AK . Pharmacokinetics and disposition of chandonium iodide in monkey . Indian J Exp Biol . May 1985 . 23 . 5 . 258–261 . 4077123 .
  14. Singh H, Bhardwaj TR, Ahuja NK, Paul D . 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. 1979 . 305–307 . 10.1039/P19790000305.
  15. Singh H, Bhardwaj TR, Paul D . Steroids and related studies. Part 48. A chandonium iodide analogue possessing an acetylcholine-like moiety. Journal of the Chemical Society, Perkin Transactions 1. 1979 . 2451 . 10.1039/p19790002451.
  16. Marshall IG, Harvey AL, Singh H, Bhardwaj TR, Paul D . The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments . J Pharm Pharmacol . Jul 1981 . 33 . 7 . 451–457 . 6115032 . 10.1111/j.2042-7158.1981.tb13831.x. 26115020 .
  17. Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG . Synthesis and neuromuscular blocking activity of 16β-piperidinosteroidal derivatives . Eur J Med Chem . Feb 2001 . 36 . 2 . 195–202 . 11311750 . 10.1016/s0223-5234(00)01205-8.
  18. Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG . Synthesis and neuromuscular blocking activity of 16β-N-methylpiperazino steroidal derivatives . Eur J Med Chem . Nov 2002 . 37 . 11 . 901–908 . 12446049 . 10.1016/s0223-5234(02)01413-7.

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