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The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Agonists of a given neurotransmitter are substances that bind to the receptor of the neurotransmitter and mimic its action. There are many ACh agonists that bind to ACh receptors and depolarize the endplate. Generally, however, they do not have the same kinetics as ACh, do not desensitize the channel in the same manner, and are not similarly affected by AChE. In low doses, they mimic the action of ACh, but in high doses, or with prolonged application, they initially cause muscular contraction followed by desensitization, accommodation, and eventual neuromuscular block. Because of this, they are termed depolarizing blocking agents. Examples of ACh agonists are nicotine, succinylcholine, and decamethonium. Succinlycholine is applied intravenously during surgery as a short-acting muscle relaxant. It has a rapid onset of about 30 s and a duration of action of 5–10 minutes. It is not hydrolyzed by AChE but by other cholinesterases normally found in the blood.
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
Succinylcholine structurally resembles ACh and thus binds and activates the ACh receptors. Succinylcholine and decamethonium are depolarizing agents that depolarize the postsynaptic membrane similar to ACh. This action produces prolong muscle fasciculation. After the initial muscle stimulation, constant depolarization results from continued binding to the nicotinic receptors (phase I). This leads to reduced receptor sensitivity and results in desensitization block that slow induce muscle paralysis (phase II). This dual block is a characteristic feature of depolarizers on all voluntary muscle. Phase II block is differently known as dual, biphasic, or antidepolarizing block and occurs clinically in response to a high dose or to prolong administration of either succinylcholine or decamethonium. It differs from phase I block which is slow in onset and similar to that produced by nondepolarizers like d-tubocurarine (Atherton, 1999; Barar, 2004; Donati and Bevan, 1996).
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
The most important drug of this class is suxamethonium (succinyldicholine) which is used as a muscle relaxant in anaesthesiology. Basically the compounds of this class are agonists for the AChR which, like ACh, have the capacity to depolarize the endplate. Three mechanisms may be responsible for the paralysis (cf. the action of AChE inhibitors as explained above): inactivation of Na+ channels, desensitization of AChRs and open channel block. The paralysis caused in man (and in the cat) by suxamethonium is primarily due to a genuine “depolarization” block caused by inactivation of the Na+ channels, although that is by no means certain for other species.76 Indeed, many drugs, including suxamethonium and decamethonium can cause desensitization of AChRs with little depolarization of the postsynaptic membrane in the muscles from many species. It should be kept in mind that depolarization block should be aggravated by AChE inhibitors, whereas the effect of these inhibitors on receptor desensitization is not a priori predictable because this depends on the rate of desensitization, transient transmitter concentration and the concentration of the agonistic drug.
Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease
Published in Xenobiotica, 2019
Ozlem Dalmizrak, Kerem Teralı, Osman Yetkin, I. Hamdi Ogus, Nazmi Ozer
Molecular docking has emerged as an important tool for the design of new anticholinesterases with enhanced affinity and selectivity. In their recent article reporting the crystal structures of human BChE in complex with five different reversible inhibitors (namely decamethonium, thioflavin T, propidium, huprine 19, and ethopropazine), Rosenberry et al. (2017) state that the active-site gorge residues of the enzyme remain immobile during ligand binding. This clearly facilitates BChE–inhibitor docking and ascertains the validity and reliability of the associated calculations. The best-selected three-dimensional model of the BChE–fluoxetine complex indicates that fluoxetine is accommodated well inside the active-site gorge of the enzyme and that it forms multiple noncovalent bonds with the critical residues lining the rim of the active-site mouth as well as the walls of the choline-binding subsite. Fluoxetine plausibly exerts its inhibitory effect on BChE by displacing the substrate from the active-site gorge through a steric mechanism. Therefore, competitive inhibition is expected to emerge as the dominant mode of inhibition in the case of BChE–fluoxetine interaction. Considering the noncholinergic pathway of AD, the binding of fluoxetine to the PAS of BChE may block the heterologous interaction of Aβ peptides with the enzyme.
A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Tereza Cristina Santos Evangelista, Óscar López, Adrián Puerta, Miguel X. Fernandes, Sabrina Baptista Ferreira, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
Because iminosugars can be protonated at physiological pH, and as such they were thought to establish cation–π interactions with the tryptophan residue in CAS of AChE in the same way as the quaternary ammonium groups of ACh and of the AChE inhibitors edrophonium and decamethonium.22 When a library of 23 iminosugars of different stereochemistry and with substituents in various positions were tested as AChE and BuChE inhibitors, some of them showed inhibition of especially BuChE in the micromolar concentration range.22 Dual binding site AChE inhibitors (i.e., such inhibitors that bind simultaneously to PAS and CAS of AChE) are attractive dual action AD drug candidates because they: (1) increase the concentration of the neurotransmitter ACh and (2) inhibit the AChE promoted formation of amyloid fibrils (a component in senile plaques23) when the PAS interacts with Aβ-proteins.24 Following this line, 1-DNJ (4) has been employed as a binding unit in the development of dual binding site ChE inhibitors when it is connected to a second aryl-substituted selenourea (exemplified by 8),25 tacrine (exemplified by 9),26 or catechol binding unit (exemplified by 10)27 (Figure 2(a)). This type of compounds was found to behave as mixed inhibitors of AChE and/or BuChE. The results were interpreted in such a way that heterodimers including a 1-DNJ moiety can bind both to the catalytic site and PAS of BuChE and AChE. Modelling studies of 9 indicated that its 1-DNJ binding unit, in its acidic form, and tacrine binding unit are able to interact simultaneously with the Trp residues in PAS and CAS, respectively.26 Modelling studies of 10, on the other hand, in complex with AChE and BuChE demonstrated that its 1-DNJ binding unit, in its acidic form, and catechol binding unit bind to the catalytic active site and PAS, respectively.27
Use of neuromuscular blocking agents in acute respiratory distress syndrome
Published in Baylor University Medical Center Proceedings, 2018
G. Tsai-Nguyen, Ariel M. Modrykamien
A neuromuscular junction is composed of a presynaptic motor axon that abuts acetylcholine receptors of skeletal muscle cells. Upon activation, the neuron releases acetylcholine, activating the skeletal muscle cell and thereby allowing the flow of sodium and potassium to trigger a muscle contraction.11 NMBAs competitively bind to the acetylcholine receptor, preventing activation of the muscle cell by acetylcholine. NMBAs are classified as depolarizing or nondepolarizing agents. Depolarizing agents mimic the effect of acetylcholine at the neuromuscular junction, and these include succinylcholine and decamethonium. Normally, when acetylcholine binds to the acetylcholine receptor on muscle cells, the channel opens for a very short duration because acetylcholinesterase rapidly degrades the transmitter in the perijunctional area.12 Conversely, depolarizing agents have a biphasic action, because they mimic acetylcholine by causing muscle contractions and, subsequently, they cause paralysis due to decreased susceptibility to degradation by acetylcholinesterase. Nondepolarizing NMBAs are also competitive antagonists at the nicotinic acetylcholine receptor but differ from depolarizing agents because they bind for longer periods of time, preventing acetylcholine from binding.13 Importantly, these agents are lipophobic, so they do not cross the blood-brain barrier. Among nondepolarizing agents, pancuronium, cisatracurium, and atracurium have all been studied in the ARDS population. Atracurium was developed in 1981 by Stenlake and colleagues.14 It is a benzylisoquinoline molecule that breaks down irreversibly at physiological pH and temperature based on the principles of Hofmann elimination.15 This characteristic presents important advantages in critically ill subjects, allowing its utilization in patients with kidney, liver, or multiorgan failure.16 However, atracurium may cause histamine release with consequent cardiovascular effects, hypotension, cutaneous flushing, and tachycardia. These effects are usually reversible within 5 minutes postadministration. As previously stated, atracurium undergoes Hofmann elimination; one of the metabolites associated with this elimination path is laudanosine, which has been reported to cross the blood-brain barrier and decrease the seizure threshold. Nevertheless, multiple studies demonstrated that concentrations of laudanosine needed to trigger seizures are much higher than those generated by doses of atracurium used in clinical practice.17 Cisatracurium is an optical isomer of atracurium and is slightly more potent. It also undergoes Hoffman elimination. Because cisatracurium causes less histamine release and concentrations of laudanosine are reportedly lower compared with atracurium, this NMBA presents hypothetical advantages.18