Narrative Review of the Role of Nondepolarizing Neuromuscular Blocking Agents in Anesthesia: Perspective 2026

Introduction

Modern anesthetic practice continually strives to optimize the control of neuromuscular block, combining rapid onset of action with predictable, short-term effects and the ability to antagonize the block quickly and without adverse effects [1–3]. So far, depolarizing agents (eg, succinylcholine) and nondepolarizing agents, including benzylisoquinolinium derivatives (eg, mivacurium) and amino-steroids rocuronium or vecuronium, have been the most commonly used agents [4,5]. However, each of these groups has its limitations. Succinylcholine should be mentioned here because of its associated numerous adverse effects, including hyperkalemia, increased intraocular pressure, and bradycardia [4,6,7]. On the other hand, nondepolarizing derivatives often require the use of a cholinesterase inhibitor to reverse the block. This effect can lead to cholinergic load of the autonomic nervous system [8]. In response to these challenges, the area of research on the new generation of nondepolarizing muscle relaxants is rapidly developing [9]. These agents have a more favorable pharmacological profile: they are characterized by a very short duration of action, predictable metabolism, and the possibility of rapid reversal of the effect by the use of specific antidotes, such as L-cysteine or calabadion. Importantly, predictable metabolism and recovery are particularly relevant in patients with organ dysfunction, because hepatic impairment can alter the potency and duration of neuromuscular blockers and the performance of reversal agents [10]. The most promising representatives of this group include gantacurium, CW002, CW011, CW1759-50, and innovative toxins such as pinnatoxin, which open new possibilities in the control of neuromuscular block during general anesthesia [9,11]. This article aims to review the role of nondepolarizing neuromuscular blocking agents in anesthesia.

Chemical structures of novel nondepolarizing neuromuscular blocking agents are presented in Figure 1.

Novel Nondepolarizing Neuromuscular Blocking Agents

Gantacurium (AV 430A; GW280430A): Preclinical Evidence and Human Data

GANTACURIUM (AV 430A; GW280430A): PRECLINICAL EVIDENCE AND HUMAN DATA:

Gantacurium (also known as AV430A or GW280430A) is a single, asymmetric enantiomeric isoquinolinium chlorofumarate diester, much like cisatracurium, and in contrast to the stereoisomeric mixtures found in atracurium and mivacurium [9]. This compound has 6 asymmetric centers, and its stereochemistry is based on the orientation of each of these sites [13]. As an ultra-short acting, nondepolarizing neuromuscular blocker, it boasts a very rapid onset and a wide safety margin [11]. Two mechanisms are involved in its elimination. The primary mechanism is nonenzymatic inactivation by L-cysteine, which reacts rapidly with the relaxant to form non-cathinone complexes. The secondary mechanism is alkaline hydrolysis, in which gantacurium slowly decomposes by cleavage of the ester bond, leading to the formation of inactive hydrolysis products [14,15]. Gantacurium, although it has shown promising results in human and animal studies, has not yet been approved by the U.S. Food and Drug Administration [16]. Clinical trials are no longer ongoing, despite the approval process having reached Phase III clinical trials [17].

ANIMAL STUDY MODEL: Gantacurium produced a dose-dependent and transient hypotensive effect at doses equivalent to 1, 3, and 5 times the 95% effective dose (ED95, a single dose of the drug that causes 95% inhibition of muscle contraction [T1] in 95% of the examined subjects), at 0.1, 0.3, and 0.5 mg/kg, respectively. Mean arterial pressure decreased by approximately 10% at 1 ED95, by an intermediate but unspecified amount at 3 ED95, and by 35% at 5 ED95, before spontaneously returning to baseline within 5 to 10 minutes without intervention. All 8 cats recovered uneventfully from anesthesia. The laryngospasm reflex was elicitable in all animals at baseline and following gantacurium 0.1 mg/kg. Administration of gantacurium 0.3 mg/kg reduced the incidence to 5 of the 8 cats, a change not statistically different from baseline. At a dose of 0.5 mg/kg, gantacurium abolished elicitable laryngospasm in all subjects (0/8), representing a statistically significant suppression vs baseline. The drug also induced transient apnea lasting less than 3 minutes without si gnificant deoxygenation. Mast cell degranulation was confirmed to underlie the transient vascular effects of gantacurium, with levels of histamine measured in the circulation (using a method described in detail by Diaz et al [18]) and correlated with the observed hypotension [19].

From studies conducted in guinea pigs, we learned that gantacurium has excellent selectivity for nicotinic receptors in the airways, with virtually no activity at muscarinic M2 or M3 sites, even at doses several times the ED95. This indicates a lower propensity to induce bronchoconstriction during anesthesia [20].

Studies have shown that in rhesus monkeys anesthetized with isoflurane, gantacurium showed an ED95 of 0.100 mg/kg, and after administration of a dose 5 times the ED95 (0.50 mg/kg), it caused neuromuscular block lasting 10.4±3.1 minutes. This potency is greater than that of the other 2 compounds, CW 002 and CW 011. With ED95 values of 0.042 mg/kg and 0.025 mg/kg, respectively, and at about 4 to 5 times their ED95 (0.15 mg/kg for CW002; 0.10 mg/kg for CW011), they gave significantly longer blocks. The duration of CW002 of 28.1±7.1 minutes is about 2.7 times longer than that of gantacurium, while the duration of CW011 block of 33.3±7.2 minutes is about 3.2 times longer [14]. Gantacurium was shown to have a very wide safety margin in a preclinical study in rhesus monkeys. The histamine-mediated effects described in the study, which were defined as 10% or more decrease in mean arterial pressure, 10% or more increase in heart rate, and facial flushing, were reported to occur only at approximately 53 ED95. Even at doses up to 27 ED95, changes in mean arterial pressure and heart rate remained below 10% of baseline [21].

At an ED95 of 0.064±0.008 mg/kg in dogs, block began after approximately 107 seconds and lasted approximately 5.2 minutes. Continuous infusion (0.012±0.002 mg·kg–1·min–1) maintained 90% to 95% block for up to 90 minutes, without changing airway pressure, lung compliance, or most cardiovascular parameters. Only heart rate was shown to increase, by approximately 14%. Even high doses (≥25 ED95) caused only a short (5–7 minutes) 10% or greater decrease in mean arterial pressure, associated with transient histamine release but without myocardial depression, bronchospasm, or pulmonary hypertension. Doses up to 3 ED95 did not cause clinically significant hemodynamic or respiratory effects, confirming a very favorable safety profile [22]. Key findings of gantacurium in animal study models are summarized in Figure 2.

HUMAN STUDY MODEL: A clinical trial conducted in healthy volunteers aimed to determine the ED95, pharmacodynamic profile, and safety of the new drug GW280430A. The ED95 was determined to be 0.19 mg/kg. The relationship between the drug dose and plasma histamine levels was also examined. When 3 ED95 was used, the concentration of histamine in the plasma doubled and exceeded 1000 pg/mL in most volunteers, which correlated with symptoms such as redness and a short-term decrease in blood pressure and increase in heart rate. Therefore, a safe dose of 2 ED95 was considered [23].

CW002: PHARMACOLOGY, PRECLINICAL SAFETY, AND HUMAN STUDIES:

CW002 is another nondepolarizing neuromuscular blocking agent with a rapid onset of action and intermediate duration of action [9]. It was synthesized in 2007–2008. To obtain a rapid onset of action, it has a very similar structure to that of gantacurium. The CW002 molecule is also a symmetric fumarate with a tetrahydroisoquinoline structure [24,25]. However, to achieve a longer duration of action, the molecule was modified so that the inactivation reaction with L-cysteine was slower; this was achieved by removing chlorine from the structure of the molecule, which significantly reduced the electronic activity of the double bond. As a result, the attachment of the thiol group of L-cysteine is less efficient, prolonging its neuromuscular blocking effects [25].

ANIMAL STUDY MODEL: In a cumulative dose study in dogs, the ED95 of CW002 was found to be 0.009 mg/kg. Full neuromuscular block was achieved within 2.6±0.9 minutes and lasted an average of 47±9 minutes at a dose 3 times greater. The studies performed showed that CW002 exerted only modest cardiovascular effects, even at very high multiples of its ED95. A small but statistically significant decrease in mean arterial pressure occurred at 25 ED95 and became more pronounced with further dosing, while decreases in heart rate and cardiac output did not occur until 50 ED95. However, at 100 ED95, a decrease in mean pulmonary artery pressure was observed. It is unlikely that these hemodynamic changes were due to histamine release, as significant histamine release was documented in only 2 animals. This underlines the favorable cardiovascular profile of the compound, even at supratherapeutic concentrations [26].

CW002 showed an ED95 of 0.042 mg/kg in a primate model. This is more than twice as potent as gantacurium. Studies have shown that it produced neuromuscular block lasting an average of 28.1±7.1 minutes when administered at a dose of 4 to 5 ED95. This is approximately 3 times longer than that achieved with gantacurium [14]. CW002 at a dose of 3 ED95 has been shown to have cardiovascular stability in the rabbit model: there were no significant changes in the area under the mean arterial pressure curve or in heart rate after its administration [18].

However, CW002 has been shown to demonstrate highly selective block of nicotinic receptors without significant effects on M2 or M3 muscarinic receptors in study of guinea pigs, despite being administered at doses up to 50 ED95. This selective nicotinic antagonism, combined with the lack of appreciable M2/M3 muscarinic activity, suggests that CW002 carries a very low risk of inducing bronchospasm or cardiovascular events during anesthesia [20]. At clinically relevant doses, CW002 has minimal cardiovascular and autonomic effects and maintains hemodynamic stability during continuous infusion. Single bolus injections produce significant changes only at very high multiples of the ED95. Specifically, a 20% decrease in mean arterial pressure requires a dose of 27 ED95, and a 20% increase in heart rate requires about 54 ED95. The compound thus demonstrates a very wide safety margin. In addition, the dose that produces 50% parasympathetic block is 0.59±0.07 mg/kg (approximately 17 ED95), whereas the dose that induces 50% sympathetic block exceeds 0.80 mg/kg (over 23 ED95) [27]. Together, these data indicate that at clinical doses used for neuromuscular block, CW002 does not significantly affect cardiovascular function or autonomic balance [27]. Key findings of CW002 in animal study model are summarized in Figure 3.

HUMAN STUDIES: Studies have shown that the effect of CW002 is predictable due to the low interindividual variability in clearance as well as its pharmacokinetic/pharmacodynamic parameters, making its administration easier to individualize. At a dose of 3 ED95, the median time to achieve 80% neuromuscular block was 0.8 minutes, confirming its rapid onset of action. This rapid effect, combined with a moderately long duration of action at the same dose of 3 ED95, produces a median time to 25% recovery of 46 minutes (range 32–65 minutes) and a time to 75% recovery of 57 minutes (range 41–80 minutes) [28]. CW002 has minimal risk of histamine release, hypotension, tachycardia, or bronchospasm at clinically relevant doses. In healthy volunteers given CW002 at doses of ED95 or higher (0.08–0.14 mg/kg), plasma histamine levels remained in the range of 103 to 866 pg/mL. This is well below the thresholds for a positive response, while mean arterial pressure remained within 10% higher or lower of the baseline value. Heart rate increased slightly (up to 7 beats per minute) in most patients (only 1 exceeded 10%). In contrast, dynamic airway compliance did not change, apart from isolated, transient decreases due to coughing or changes in the ventilator settings [29].

CW011: PRECLINICAL EVIDENCE AND REMAINING KNOWLEDGE GAPS:

CW011 is an asymmetrical maleate non-halogenated olefinic diester analogue of gantacurium (like CW002, a symmetrical fumarate) that exhibits a rapid onset of action but an intermediate duration of action [9,11]. An in vitro study showed that this agent undergoes L-cysteine adduction more slowly than does gantacurium [14].

ANIMAL STUDY MODEL: The ED95 of CW011 is 0.025 mg/kg, making CW011 approximately 4 times more potent than gantacurium. At 4 to 5 ED95 (0.10 mg/kg), the total duration of action (defined as onset until 95% recovery of single twitch response) averaged 33.3±7.2 minutes, which is approximately 3 times longer than that of gantacurium [14]. However, to date, no clinical studies have been conducted to confirm these findings in humans [30].

CW1759-50: PRECLINICAL PROFILE AND DEVELOPMENT STATUS:

CW 1759-50 is a bis-quaternary benzyl-isoquinolinium diester linked via a maleinate bridge, featuring 2 positively charged nitrogen centers and 2 ester bonds to maleic acid. It undergoes very rapid L-cysteine adduction (half-life≈2.3 min), which confers its ultra-short duration of action; this compound is currently undergoing clinical trials in the United States [31,32].

ANIMAL STUDY MODEL: CW 1759-50 showed slightly higher potency in the monkey model (ED95 0.069±0.02 mg/kg vs 0.081±0.05 mg/kg for gantacurium; P=0.006), with almost identical onset time (onset 94±9 s vs 97±12 seconds; P=0.573) and comparable ultra-short duration of action (to 95% recovery: 8.2±1.5 minutes for CW 1759–50 vs 7.4±1.9 minutes for gantacurium; P=0.355). Because of its properties, CW1759-50 may require lower doses to attain rapid and short-lasting muscle relaxation [31]. CW1759-50 is characterized by reduced histamine effects and a stable hemodynamic profile, superior to gantacurium in terms of cardiovascular safety; it induces no significant changes in mean arterial pressure, even up to 100 ED95, indicating a much larger safety margin. No significant changes in heart rate were observed even at doses up to 58 ED95 [31].

PINNATOXINS AS EXPERIMENTAL NEUROMUSCULAR BLOCKERS: CURRENT EVIDENCE:

Pinnatoxins are highly toxic compounds belonging to the cyclic imines family, produced by some species of dinoflagellates and accumulated in marine shells [33]. Pinnatoxins competitively block the acetylcholine binding site on nicotinic receptors in the motor end plate, preventing the ion channel from opening. As a result, there is no depolarization of the muscle fiber or contraction [34]. To date, these compounds have only been used in preclinical studies, mainly in animal preparations and in vitro models.

ANIMAL STUDY MODEL: Studies in mice have shown that intramuscular administration of pinnatoxins A and G induced a rapid, dose-dependent inhibition of neuromuscular transmission, as determined by a compound motor action potential amplitude decrease of 50% at a dose of approximately 3 nmol/kg. The block was completely reversible within 6 to 8 hours [35].

Reversal of Neuromuscular Block: Emerging Strategies

L-CYSTEINE:

Fumarate derivatives such as gantacurium, CW002, CW011, and CW1759-50 are nondepolarizing neuromuscular blockers inactivated by L-cysteine, which binds to the drug’s carbon-carbon double bond, forming a stable thioether adduct that prevents binding to acetylcholine receptors. This adduct then slowly hydrolyses into inactive fragments, enabling rapid and complete reversal of neuromuscular block [14,31].

The duration of neuromuscular block in monkeys correlated inversely with the rate of L-cysteine adduction in vitro. After administration of doses of 4 to 5 ED95 gantacurium, CW002, and CW011, a more rapid binding occurs, which leads to a shorter block, with gantacurium exhibiting the fastest adduction and the shortest block, while CW002 and CW011 bind more slowly and have a longer duration of action. After administration of exogenous L-cysteine (10–50 mg/kg), there is a chemically driven complete reversal of neuromuscular block regardless of its depth. This requires less than 2 to 3 minutes for all 3 compounds. The speed of reversal provides an “on demand” option that is both faster and more complete than with traditional agents such as neostigmine or edrophonium [14].

Another study confirmed this property, which is characterized by the fact that intravenous L-cysteine (50 mg/kg) causes rapid, reliable clinical reversal of CW002-induced neuromuscular block. It also shortens the duration of block from 47±9 minutes to 3.7±0.6 minutes after a dose of 3 ED95. It should be noted that it does so without recurrence of block, demonstrating permanent inactivation of the drug [26]. In the studies that focused on the properties of L-cysteine in reversing CW1759-50–induced neuromuscular block, the data were presented as follows: a single intravenous dose of L-cysteine (30 mg/kg), given after a 3-ED95 CW1759-50 bolus, shortened the time to 95% recovery of contractile force from 12.6±1.8 minutes to 4.5±0.9 minutes. This is a rapid, predictable reversal that occurs with less than 10% hemodynamic variability, thus making L-cysteine a simple and safe antidote for rapid recovery of neuromuscular function [31].

There are currently no human studies to support the safety of L-cysteine in reversing neuromuscular block induced by the new muscle relaxants. Although L-cysteine is not toxic at therapeutic doses, some chemically modified S-conjugates may be harmful in larger doses: in neurons, they induce oxidative stress and damage in vitro; in the kidney, β-lyase-activated halogenated conjugates damage proximal tubule cells; and some interfere with mitochondrial enzymes, disrupting cellular energy metabolism [36].

CALABADION:

Calabadion is an acyclic cucurbit[n]uril derivative that tightly binds aminosteroidal and benzylisoquinolinium neuromuscular blockers by forming host-guest complexes, immediately binding free relaxant molecules in the plasma, thus reducing their concentration at the motor end plate and restoring neuromuscular conduction in several dozen seconds [37].

Calabadion1, due to its very high binding affinity (Ka approximately 106–107 M–1), binds free rocuronium and cisatracurium molecules almost immediately after administration, which in a rat model allowed for the restoration of spontaneous breathing within seconds (15±8 seconds for rocuronium, 47±13 seconds for cisatracurium) and achieving train-of-four (TOF) of 0.9 or more in less than 1.5 minutes. For comparison, neostigmine reverses the block in 2.8 to 4.6 minutes, ie, approximately 10 to 20 times slower. Additionally, neostigmine requires significant neuromuscular recovery (presence of at least TOF count of 3 or 4) for rapid (<10 minutes) antagonism. In terms of safety, calabadion1 does not significantly affect heart rate, blood pressure, or blood gas parameters, does not induce recurrent neuromuscular block within at least an hour, and is excreted almost entirely in urine within 60 minutes. The lack of interaction with cholesterol and a low toxicity profile in vitro and a high tolerated dose in vivo also suggest good tolerance [37].

Calabadion2 reverses neuromuscular block induced by both steroidal (rocuronium, vecuronium) and benzylisoquinoline (cisatracurium) agents faster than sugammadex - at doses of 40 to 80 mg/kg, the time to spontaneous ventilation was about 14 to 16 seconds, and TOF greater than 0.9 was achieved within a few seconds. Calabadion2 binds rocuronium with an approximate association constant of Ka=3.4×109 M–1, which represents about 90-times higher affinity than sugammadex (Ka=3.8×107 M–1). In animal studies, no hemodynamic changes or recurarization were observed, and after administration of calabadion2, succinylcholine retained full efficacy upon re-administration. The drug is rapidly excreted in urine (≥49% within an hour) without significant metabolism, which minimizes the risk of interactions in the postoperative period [38].

Discussion and Clinical Implications

The newly introduced nondepolarizing muscle relaxants and agents for reversal of neuromuscular block, despite promising research results, are still not available for general clinical use. Key features of the described agents are presented in Table 1. Of the fumarate derivatives, gantacurium is the closest to being approved for use; however, further development has been stopped, and there are currently no human studies involving this drug. Despite promising results in animal models in terms of drug safety, in human studies, gantacurium at therapeutic doses, ie, 3 ED95 caused the release of histamine from mast cells, resulting in cardiovascular system changes. The analogue of gantacurium, CW002, has a good chance of being approved for general use. In animal models and during clinical trials, it showed a favorable safety profile and does not cause histamine release in therapeutic doses in humans, having only minor effects on the cardiovascular system. Other muscle relaxants, such as CW011, CW1759-50, and pinnatoxin, are in the very early stages of research; they showed high efficacy in animal models, but there are no planned human studies yet. Fumarate derivatives have great potential for approval for general use, especially due to their inactivation mechanism: through naturally occurring L-cysteine. This method of inactivation was effective in animal models; however, but no human studies have been conducted to date to confirm the efficacy and safety of this agent. L-cysteine is considered a safe agent, but there are concerns about the potential neuro- and nephrotoxicity of L-cysteine derivatives. The need to develop new muscle relaxants with a very short duration of action is also questioned, due to the potential use of calabadion, which is highly effective and very rapid in reversing the neuromuscular block already induced by existing and commercially available steroidal and benzylisoquinolinium agents. Even if none of the currently existing medications is free from adverse effects, available neuromuscular blocking agents have a long history of efficacy and safety. Future directions for studies in this field should address the features of the ideal blocking agent, which are briefly mentioned in Figure 4.

Future Directions

Future research should concentrate on moving the most mature candidates and reversal concepts into clinically meaningful evaluation, because the key unanswered questions are no longer purely mechanistic but practical: predictability, safety, and usability in real-world anesthesia [4,25]. CW002 should be a priority target, since dose-escalation and pharmacokinetic/pharmacodynamic work in healthy volunteers support rapid onset with an intermediate duration and a low signal for clinically relevant histamine release or cardiopulmonary instability at studied doses [28]. The next logical step is therefore confirmatory trials in surgical patients that use standardized quantitative neuromuscular monitoring and report clinically actionable endpoints (eg, time to acceptable intubating conditions, time to TOF ≥0.9, interindividual recovery variability, and residual blockade), ideally including pragmatic comparisons against established rocuronium-based approaches and contemporary reversal strategies [4,6,39]. This should include careful standardization of the monitoring device and measurement site, as recent clinical data show that different quantitative monitors and limb placements can yield non-identical recovery profiles [40]. In parallel, CW1759-50 warrants a focused translational “go/no-go” pathway, because primate data suggest ultra-short action with much reduced circulatory effects compared with gantacurium and demonstrable antagonism by L-cysteine, making it a plausible candidate for human testing if these advantages translate [31,41]. The gantacurium experience should also be treated as a clear development lesson: even with strong preclinical performance, human studies showed dose-related, histamine-suggestive cardiovascular effects at higher multiples of ED95, underscoring the need for early, rigorous hemodynamic and histamine-response characterization during dose finding for any future ultra-short neuromuscular blocking agent programs [23]. Because being able to stop neuromuscular block quickly and reliably may matter just as much as choosing the right blocker, future clinical research should directly evaluate intravenous L-cysteine as a reversal agent for olefinic isoquinolinium diesters, building on strong preclinical evidence that it can rapidly inactivate these drugs through chemical adduction and produce fast, complete reversal regardless of block depth [14]. At the same time, these studies should be designed to carefully document safety in perioperative patients, since human data on L-cysteine used specifically for neuromuscular blocking agent reversal are still lacking, and there are theoretical concerns that some cysteine-related metabolites or conjugates could have neuro- or nephrotoxic effects at higher exposures, which should be actively monitored with appropriate clinical and laboratory endpoints [36]. Finally, calabadion-based reversal deserves continued translational evaluation, since animal studies indicate rapid and effective reversal of steroidal and benzylisoquinoline neuromuscular blocking agents and, for calabadion2, faster reversal than sugammadex in comparative models, an advance that could shift innovation away from ever shorter-acting relaxants and toward more predictable, controllable neuromuscular blockade in routine practice [37,38].

Conclusions

It is not expected that a new nondepolarizing muscle relaxant will be developed and approved for general clinical use in the near future. Currently, most of the new potent neuromuscular blocking agents are in the early stages of research; however, as gantacurium illustrated, despite very favorable results in animal models, the translation to humans and routine clinical use requires decades of testing and detailed clinical trials.