Development of ultra short‐acting muscle relaxant agents: History, research strategies, and challenges

Gyermek, László

doi:10.1002/med.20036

Cited by 19 publications

(5 citation statements)

References 164 publications

(211 reference statements)

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“…342 Gantacurium chloride (AV430A, GW280430A) 111 is a nondepolarizing ultra-short-acting neuromuscular blocker (NMB) inspired by curare alkaloids that was developed by GSK and licensed to Avera Pharmaceuticals in 2002. [343][344][345][346][347][348] NMBs are used as adjuncts to anaesthesia to provide skeletal muscle relaxation during surgery and to facilitate tracheal intubation. Another ultra-short-acting depolarizing NMB, succinylcholine, is used routinely but can produce a number of potentially dangerous side effects.…”

Section: Halted or Discontinued Compounds In Neurological Diseasesmentioning

confidence: 99%

Natural products to drugs: natural product-derived compounds in clinical trials

2008

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Natural product and natural product-derived compounds that are being evaluated in clinical trials or are in registration (as at 31st December 2007) have been reviewed, as well as natural product-derived compounds for which clinical trials have been halted or discontinued since 2005. Also discussed are natural product-derived drugs launched since 2005, new natural product templates and late-stage development candidates.

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Section: Halted or Discontinued Compounds In Neurological Diseasesmentioning

confidence: 99%

Natural products to drugs: natural product-derived compounds in clinical trials

2008

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“…The onset of action at the neuromuscular junction depends on the degree of lipophilicity, binding to proteins, the rate at which the drug reaches the neuromuscular junction, the potency of the drug, its metabolism, and its excretion [ 43 ]. NMBDs reach their maximum plasma concentration immediately after intravenous administration; however, the maximal blocking effect may be delayed for most NMBDs.…”

Section: Buffered Diffusion To the Effect Sitementioning

confidence: 99%

Factors that affect the onset of action of non-depolarizing neuromuscular blocking agents

Kim

Sung

Yang

2017

Korean J Anesthesiol

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Neuromuscular blockade plays an important role in the safe management of patient airways, surgical field improvement, and respiratory care. Rapid-sequence induction of anesthesia is indispensable to emergency surgery and obstetric anesthesia, and its purpose is to obtain a stable airway, adequate depth of anesthesia, and appropriate respiration within a short period of time without causing irritation or damage to the patient. There has been a continued search for new neuromuscular blocking drugs (NMBDs) with a rapid onset of action. Factors that affect the onset time include the potency of the NMBDs, the rate of NMBDs reaching the effect site, the onset time by dose control, metabolism and elimination of NMBDs, buffered diffusion to the effect site, nicotinic acetylcholine receptor subunit affinity, drugs that affect acetylcholine (ACh) production and release at the neuromuscular junction, drugs that inhibit plasma cholinesterase, presynaptic receptors responsible for ACh release at the neuromuscular junction, anesthetics or drugs that affect muscle contractility, site and methods for monitoring neuromuscular function, individual variability, and coexisting disease. NMBDs with rapid onset without major adverse events are expected in the next few years, and the development of lower potency NMBDs will continue. Anesthesiologists should be aware of the use of NMBDs in the management of anesthesia. The choice of NMBD and determination of the appropriate dosage to modulate neuromuscular blockade characteristics such as onset time and duration of neuromuscular blockade should be considered along with factors that affect the effects of the NMBDs. In this review, we discuss the factors that affect the onset time of NMBDs.

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“…Design of the mono-and bis-quaternary NMBAs Despite that the NMBAs were built on various structural cores (steroids, tetrahydroisoquinoliniums, tropines, and truxillic acids), they all follow an 'essential rule' of SAR: Two quaternary nitrogen atoms span a distance (denoted as N-N distance) varying from 1 nm to 1.6 nm; the potency is compromised when one of the nitrogen is tertiary (3,6,20). As to the steroidal NMBA, the androstane skeleton adds two extra structural bonuses for improving the activity: 1) the rigid and bulky structure can maintain the N-N distance and the non-depolarizing mechanism and 2) the conformation of the ACh-like moiety in D-ring (16b-ammonium-17b-ol) largely resembles the 'gauche' conformation of the nAChR-bound ACh (6,21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Non-depolarizing NMBAs are competing with acetylcholine (ACh) for AChR to relax skeletal muscle, and induce less side-effects than depolarizing ones such as succinylcholine which depolarizes motor endplates to interrupt the normal response of AChRs to ACh (2). Various scaffolds have been studied for non-depolarizing NMBAs (3). As the steroid scaffold (Figure 1) is rigid, hydrophobic and easy to be modified in various positions (positions 2, 3, 16, and 17), many steroidal NMBAs have been intensively studied during the past decades.…”

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confidence: 99%

Steroidal Ammonium Compounds as New Neuromuscular Blocking Agents

Rao

Tang

et al. 2016

Chem Biol Drug Des

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Neuromuscular blocking agents are widely used as an anesthesia auxiliary in surgery, which induce relaxation of skeletal muscles by blocking signal transmission at the neuromuscular junction. Many neuromuscular blocking agents s were developed over the past decades, but none of them fully meets the needs of the clinic by various reasons. In this study, a series of quaternary ammonium steroidal neuromuscular blocking agents were synthesized and evaluated on isolated mouse phrenic nerve-hemidiaphragms for their bioactivities. The initial separation of mono- and bis-quaternary ammonium compounds turned out to be very challenging on regular silica gel chromatography. Therefore, a facile purification method, in which the silica gel was pretreated with methanolic sodium bromide solution, was finally achieved. Compounds 3g (0.36 μm) and 4g (0.37 μm) exhibited excellent neuromuscular blocking activities, which were about sixfold to sevenfold higher in potency than that of rocuronium (2.50 μm). In addition, other bis-quaternized compounds also showed good potencies close to that of rocuronium. Furthermore, the preliminary structure-activity relationship of this series was also elucidated. Benzyl group was found to be a promising quaternary group in this series.

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Development of ultra short‐acting muscle relaxant agents: History, research strategies, and challenges

Cited by 19 publications

References 164 publications

Natural products to drugs: natural product-derived compounds in clinical trials

Natural products to drugs: natural product-derived compounds in clinical trials

Factors that affect the onset of action of non-depolarizing neuromuscular blocking agents

Steroidal Ammonium Compounds as New Neuromuscular Blocking Agents

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