Candocuronium iodide

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Candocuronium iodide
Candocuronium iodide.png
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
category
  • Not applicable
Legal status
  • Discontinued from clinical development
Routes of
administration
IV
Pharmacokinetic data
Bioavailability 100% (IV)[citation needed]
Identifiers
CAS Number 54278-85-2 YesY
ATC code none
PubChem CID: 71537
ChemSpider 64610 N
UNII SC80GNP08C N
ChEMBL CHEMBL2106112 N
Synonyms Chandonium iodide; HS-310
Chemical data
Formula C26H46I2N2
Molecular mass 640.47 g/mol
  • [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 N
  • Key:GGAGIPMNQXAXNH-XDMKMBKMSA-L N
 NYesY (what is this?)  (verify)

Candocuronium iodide (INN, formerly chandonium, HS-310)[1] is the prototypical[editorializing][not verified in body] 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 bromide.[2][3][4][5] Candocuronium 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.[1]


Background

As with other established 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 "the Holy Grail of neuromuscular blocking agents":[attribution needed] a non-depolarizing replacement for the most popular clinically used 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 HS-342 structure[how?] led to two other notable agents,[editorializing] 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.[editorializing][10][11][12][13]

Modifications to the candocuronium design

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?][14] whose onset and duration were indinguishable from candocuronium, but, unfortunately,[editorializing] all demonstrated profound vagolytic effects and much weaker potencies than candocuronium.[11] 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.[15] Unfortunately, upon further preclinical evaluation in the cat and isolated preparations,[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] 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.

References

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  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.
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External links