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Alcuronium

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Stanislav Tucek – 1st expert on this subject based on the ideXlab platform

  • protection by Alcuronium of muscarinic receptors against chemical inactivation and location of the allosteric binding site for Alcuronium
    Journal of Neurochemistry, 2002
    Co-Authors: Jan Jakubík, Stanislav Tucek

    Abstract:

    : We have found earlier that the neuromuscular blocker Alcuronium binds to cardiac muscarinic receptors simultaneously with their specific antagonist [3H]methyl-N-scopolamine ([3H]NMS) and allosterically increases their affinity to this ligand. Nothing is known about the allosteric site with which Alcuronium interacts. To gain an insight, we have now investigated how the binding of [3H]NMS is affected by agents known to modify specific residues in proteins and how their effects are altered by Alcuronium. Reagents that covalently modify the tyrosyl residues (p-nitrobenzenesulfonyl fluoride and 4-chloro-7-nitrobenzofurazan) and the carboxyl groups of aspartate and glutamate [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-dicyclohexylcarbodiimide, and N-ethyl-5-phenylisoxazolium-3′-sulfonate] blocked the binding of [3H]NMS to receptors in rat heart atria. Their action was probably due to the modification of tyrosyl and aspartyl residues directly in the muscarinic binding sites because it was antagonized by atropine and carbamoylcholine. Alcuronium and gallamine, another allosteric ligand, also protected the [3H]NMS binding sites against the inactivation by tyrosine- and carboxyl-directed chemical modifiers just as well as by benzilylcholine mustard, known to attach covalently to the muscarinic binding sites. Protection by Alcuronium has also been observed on cerebrocortical muscarinic receptors. The effect of Alcuronium indicates that the drug interferes with the access of chemical modifiers to the muscarinic sites. In view of the unspecific nature of most of the modifiers used (with regard to muscarinic mechanisms), the protection by Alcuronium appears to be best explained on the assumption that the drug binds in close vicinity of the “classical” muscarinic site and sterically blocks the access to this site.

  • changes of cooperativity betweenn methylscopolamine and allosteric modulators Alcuronium and gallamine induced by mutations of external loops of muscarinic m3 receptors
    Molecular Pharmacology, 2001
    Co-Authors: Alena Krejci, Stanislav Tucek

    Abstract:

    To clarify the involvement of specific domains of muscarinic receptors in the action of allosteric modulators, muscarinic M 3 receptors (on which allosteric interactions are weak) were genetically modified to become more similar to M 2 receptors (on which allosteric interactions are strong) and were expressed in COS-7 cells. Affinity for allosteric modulator gallamine was enhanced 25- to 50-fold by modifications of the third external loop (o3) and the negative effect of gallamine on the affinity for classical antagonist N -[ 3 H]methylscopolamine ([ 3 H]NMS) was augmented. Affinity for Alcuronium became 3-fold higher after the o3 loop of M 3 receptors was made identical with the o3 loop of M 2 receptors, and Alcuronium acquired positive influence on the affinity for [ 3 H]NMS. This is the first instance of inducing positive cooperativity on muscarinic receptors by genetic manipulation. Transferring whole o2 loop from M 2 to M 3 receptors substantially enhanced affinities for gallamine and Alcuronium without augmenting their negative action on [ 3 H]NMS binding. In contrast, effects of simply adding two negative charges into the o2 loop of M 3 receptors were small. Removal of Arg from o1 loop abolished the negative effect of gallamine but not of Alcuronium on [ 3 H]NMS binding at equilibrium. Data point to an important role of o3 loop in the mechanism of the positive and negative cooperativity between [ 3 H]NMS and Alcuronium and gallamine, respectively, and in the binding of both modulators to M 2 receptors and reveal independence between mutation-induced changes in the affinity for a modulator and in the magnitude and direction of the allosteric effect of the modulator.

  • Interactions between Allosteric Modulators and 4-DAMP and Other Antagonists at Muscarinic Receptors: Potential Significance of the Distance between the N and Carboxyl C Atoms in the Molecules of Antagonists
    Neurochemical Research, 2001
    Co-Authors: Michaela Lysíková, Zdeněk Havlas, Stanislav Tucek

    Abstract:

    Allosteric enhancement of the affinity of muscarinic receptors for their ligands offers a new way to influence cholinergic neurotransmission. The structure of the allosteric binding domain(s) and the features of agonists, antagonists and modulators which determine the occurrence of either positive or negative cooperativity require clarification. We tested interactions between allosteric modulators Alcuronium, strychnine and brucine and eight antagonists at muscarinic receptors expressed in CHO cells. In experiments with unlabeled antagonists, all three modulators enhanced the affinity for 4-diphenylacetoxy-N-dimethylpiperidinium (4-DAMP) at the M_2 receptors, and strychnine did so also at the M_4 receptors. Positive interactions were also observed between Alcuronium and L-hyoscyamine (M_2) and scopolamine (M_2), between strychnine and butylscopolamine (M_4), L-hyoscyamine (M_2 and M_4) and scopolamine (M_4), and between brucine and scopolamine (M_2). Positive effects of Alcuronium, strychnine and brucine on the affinity of the M_2 receptors for 4-DAMP have been confirmed by direct measurements of the binding of [^3H]-4-DAMP. A comparison of molecular models of several antagonists which are esters revealed that antagonists in which the distance between the N and the carboxyl C atoms corresponds to five chemical bonds are more likely to display positive cooperativity with Alcuronium at the M_2 receptors than the antagonists in which the N-carboxyl C distance corresponds to four chemical bonds.

O A Meretoja – 2nd expert on this subject based on the ideXlab platform

  • maintenance requirement of Alcuronium in paediatric patients
    Anaesthesia and Intensive Care, 1990
    Co-Authors: O A Meretoja, T C K Brown

    Abstract:

    : Seventeen paediatric patients from 0.3 to 19 years old were studied to determine the individual dose-response curves and the maintenance requirements of Alcuronium during N2O-O2-opioid anaesthesia. Alcuronium 300 micrograms/kg maintained the mean (SD) neuromuscular block at 90-95% for 62 34 min). This time was longest in patients of less than 1 year of age (92 min). The hourly maintenance requirement of Alcuronium was 0.41 (0.12) times the individual ED95 dose. This value was comparable in infants, children and adolescents and indicates similar duration of effect of Alcuronium in all paediatric age groups.

  • does suxamethonium influence the subsequent dose requirements of Alcuronium and its reversibility in children
    Anaesthesia and Intensive Care, 1990
    Co-Authors: T C K Brown, O A Meretoja, D Clare, B Bell

    Abstract:

    : Suxamethonium is often used for intubation prior to the use of a nondepolarizing muscle relaxant. This study was performed to determine whether suxamethonium altered the dose of Alcuronium required to produce neuromuscular block. The findings were that suxamethonium 1.0 mg/kg did not alter the depth, duration or reversibility of block if given before Alcuronium 0.3 mg/kg. Reversal with neostigmine was more rapid following 50 micrograms/kg than after 25 micrograms/kg. If recovery from neuromuscular block was greater than 25 per cent, the lower dose produced satisfactory reversal, whether or not suxamethonium had been given previously.

  • dose response of Alcuronium and d tubocurarine in infants children and adolescents
    Anaesthesia and Intensive Care, 1990
    Co-Authors: O A Meretoja, T C K Brown, D Clare

    Abstract:

    : Seventy neonatal to adolescent general surgical patients were studied to create an individual dose-response curve for the long-acting neuromuscular blocking agents, Alcuronium and d-tubocurarine. The mean (SEM) ED95 of Alcuronium was 196 (9), 271 (13) and 243 (8) micrograms/kg in infants, children and adolescents, respectively (P less than 0.01). d-tubocurarine showed a similar age dependent dose-response relationship. ED95 doses were 414 (40), 499 (41) and 445 (31) micrograms/kg, respectively. The onset time (time from intravenous administration to maximal effect) following equipotent dosages was 40-50% shorter in infants than in children or adolescents (1.5 vs 2.7 minutes, P less than 0.05).

Jan Jakubík – 3rd expert on this subject based on the ideXlab platform

  • protection by Alcuronium of muscarinic receptors against chemical inactivation and location of the allosteric binding site for Alcuronium
    Journal of Neurochemistry, 2002
    Co-Authors: Jan Jakubík, Stanislav Tucek

    Abstract:

    : We have found earlier that the neuromuscular blocker Alcuronium binds to cardiac muscarinic receptors simultaneously with their specific antagonist [3H]methyl-N-scopolamine ([3H]NMS) and allosterically increases their affinity to this ligand. Nothing is known about the allosteric site with which Alcuronium interacts. To gain an insight, we have now investigated how the binding of [3H]NMS is affected by agents known to modify specific residues in proteins and how their effects are altered by Alcuronium. Reagents that covalently modify the tyrosyl residues (p-nitrobenzenesulfonyl fluoride and 4-chloro-7-nitrobenzofurazan) and the carboxyl groups of aspartate and glutamate [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-dicyclohexylcarbodiimide, and N-ethyl-5-phenylisoxazolium-3′-sulfonate] blocked the binding of [3H]NMS to receptors in rat heart atria. Their action was probably due to the modification of tyrosyl and aspartyl residues directly in the muscarinic binding sites because it was antagonized by atropine and carbamoylcholine. Alcuronium and gallamine, another allosteric ligand, also protected the [3H]NMS binding sites against the inactivation by tyrosine- and carboxyl-directed chemical modifiers just as well as by benzilylcholine mustard, known to attach covalently to the muscarinic binding sites. Protection by Alcuronium has also been observed on cerebrocortical muscarinic receptors. The effect of Alcuronium indicates that the drug interferes with the access of chemical modifiers to the muscarinic sites. In view of the unspecific nature of most of the modifiers used (with regard to muscarinic mechanisms), the protection by Alcuronium appears to be best explained on the assumption that the drug binds in close vicinity of the “classical” muscarinic site and sterically blocks the access to this site.

  • Effects of an Agonist, Allosteric Modulator, and Antagonist on Guanosine-γ-[35S]thiotriphosphate Binding to Liposomes with Varying Muscarinic Receptor/Go Protein Stoichiometry
    Molecular Pharmacology, 1998
    Co-Authors: Jan Jakubík, Tatsuya Haga, Stanislav Tucek

    Abstract:

    We investigated whether Alcuronium, an allosteric modulator of muscarinic acetylcholine receptors, can induce receptor-mediated activation of Go proteins in liposomal membranes incorporating purified M2 receptors and Goproteins and whether its action is affected by the receptor/Go protein (R/Go) ratio. The binding of guanosine-γ-[35S]thiotriphosphate ([35S]GTPγS) served as the indicator of G protein activation. It was stimulated by empty receptors at high receptor densities, and the dose-response curve was shifted to the left by the agonist carbachol and to the right by the antagonist atropine. At an R/Go ratio of 300:100, the rate of [35S]GTPγS binding was the same in the presence or absence of 0.1 mm carbachol. Alcuronium increased the binding of [35S]GTPγS at R/Go ratios of 10:100, similar to previous observations on intact cells expressing muscarinic receptors at different densities. The apparent biphasicity of Alcuronium action indicates that the allosteric modulator has at least two effects on muscarinic receptor/G protein interaction but its mechanistic basis is unclear. The “active state” of muscarinic receptors induced by Alcuronium probably is different from that induced by carbachol. Changes in the densities of receptors and Goproteins had little effect on the kinetics of [35S]GTPγS binding and on receptor affinity for carbachol, provided the R/Go ratio was kept constant. This suggests that the receptors and G proteins are located in microdomains in which their concentrations remain constant, despite variations in the amounts of lipidic membranes in the system.

  • subtype selectivity of the positive allosteric action of Alcuronium at cloned m1 m5 muscarinic acetylcholine receptors
    Journal of Pharmacology and Experimental Therapeutics, 1995
    Co-Authors: Jan Jakubík, Lucie Bacakova, Esam E Elfakahany, Stanislav Tucek

    Abstract:

    The neuromuscular blocking drug Alcuronium was found earlier to increase the affinity of muscarinic receptors for methyl-N-scopolamine (NMS). This effect could be observed in some but not in other tissues. Subtype selectivity of the positive allosteric action of Alcuronium was now investigated in radioligand binding experiments in Chinese hamster ovary (CHO) cells stably transfected with the genes encoding the M1-M5 subtypes of muscarinic receptors. Alcuronium had a particularly high affinity for the M2 receptor subtype (Kd = 0.6 microM) and its affinity for muscarinic receptor subtypes diminished in the order M2 > M4 = M3 > M1 > M5. Alcuronium allosterically increased the binding of (3H)NMS to membranes containing receptors of the M2 (cooperativity factor alpha = 0.38) and M4 subtypes (alpha = 0.72) and inhibited the binding of (3H)NMS to membranes containing receptors of the M1, M3 and M5 subtypes (alpha = 3.35-4.35). The positive effects of Alcuronium could also be observed in experiments with (3H)NMS binding to intact whole cells, indicating that the positive allosteric action of Alcuronium occurs by Alcuronium binding to receptor domains that are accessible from the extracellular space. Alcuronium diminished the affinity for (3H)quinuclidinyl benzilate [(3H)QNB] at all five subtypes of muscarinic receptors and slowed down the dissociation of both (3H)NMS and (3H)QNB; its decelerating effect on radioligand dissociation was most pronounced at the M2 receptor subtype. Differences between the effects of Alcuronium on individual muscarinic receptor subtypes are apparently responsible for differences between the allosteric effects of Alcuronium on muscarinic receptors in various tissues that had been described previously.