Candocuronium iodide

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 by blocking the binding 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.

Candocuronium iodide

Clinical data
Other names	Chandonium 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
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
CAS Number	54278-85-2 Y
PubChem CID	71537
ChemSpider	64610 N
UNII	SC80GNP08C
ChEMBL	ChEMBL2106112 N
CompTox Dashboard (EPA)	DTXSID60969306
Chemical and physical data
Formula	C26H46I2N2
Molar mass	640.477 g·mol−1
3D model (JSmol)	Interactive image
SMILES [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 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
NY (what is this?)  (verify)

Medical use and discontinuation

Candocuronium was clinically evaluated in India for providing skeletal muscle relaxation during surgery, easing tracheal intubation, and assisting with mechanical ventilation.^[3] Clinical studies reported a rapid onset of action with a short duration. Development was discontinued due to cardiovascular side effects, notably 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] Research indicated that candocuronium had minimal ganglion-blocking activity and higher 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 azasteroid. 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 turbocurarine, was precluded from clinical trials because it exhibited considerable ganglion-blocking activity, which would potentially lead 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 better neuromuscular blocking profile and had 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]}