Rapid Chemical Antagonism of Neuromuscular Blockade by l-Cysteine Adduction to and Inactivation of the Olefinic (Double-bonded) Isoquinolinium Diester Compounds Gantacurium (AV430A), CW 002, and CW 011

Abstract

L-cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous L-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time.

Novel neuromuscular blocking drugs and antagonists

“…1) [12]. Subsequent invitro investigation revealed this interaction to be relatively fast (reaction half-time of $15 s) and to yield an adduction product with very little affinity for nicotinic receptors at the motor end plate [13,14]. This molecular inactivation by L-cysteine involves a nonenzymatic chemical reaction between the cysteine thiol group and the central 'olefinic' double bond in the fumarate forming a heterocyclic ring between the two quaternary heads (Fig.…”

“…This molecular inactivation by L-cysteine involves a nonenzymatic chemical reaction between the cysteine thiol group and the central 'olefinic' double bond in the fumarate forming a heterocyclic ring between the two quaternary heads (Fig. 1) [13]. The presence of a chloride within the central fumarate appears to facilitate this reaction.…”

“…For CW002, the resulting adduction product retains some, but very low, affinity for neuromuscular nicotinic receptors, with potency for neuromuscular blockade decreased 70À100-fold [13]. The adduct then is hydrolyzed to fragments that are 500À1000-fold less potent than the parent compound.…”

“…The presence of a chloride within the central fumarate appears to facilitate this reaction. Slower breakdown via pH sensitive ester hydrolysis adjacent to the chloride also occurs, yielding two inactive ester hydrolysis products [13].…”

“…4, CW002 is structurally similar to gantacurium with the exception of two fewer 1-benzyl methoxy groups, and no chloride to facilitate the cysteine sulfhydryl group interaction with the central olefinic double bond. Consequently, in-vitro measurements indicate an 11-min reaction half-time for cysteine adduction to CW002 [13].…”