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Stanislav Tucek - One of the best experts on this subject based on the ideXlab platform.
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protection by Alcuronium of muscarinic receptors against chemical inactivation and location of the allosteric binding site for Alcuronium
Journal of Neurochemistry, 2002Co-Authors: Jan Jakubík, Stanislav TucekAbstract:: 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.
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changes of cooperativity betweenn methylscopolamine and allosteric modulators Alcuronium and gallamine induced by mutations of external loops of muscarinic m3 receptors
Molecular Pharmacology, 2001Co-Authors: Alena Krejci, Stanislav TucekAbstract: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.
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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, 2001Co-Authors: Michaela Lysíková, Zdeněk Havlas, Stanislav TucekAbstract: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.
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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, 1998Co-Authors: Jan Jakubík, Tatsuya Haga, Stanislav TucekAbstract: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.
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the effects of brucine and Alcuronium on the inhibition of 3h acetylcholine release from rat striatum by muscarinic receptor agonists
British Journal of Pharmacology, 1998Co-Authors: Vladimir Doležal, Stanislav TucekAbstract:1 Radioligand binding experiments indicate that the affinity of muscarinic receptors for their agonists may be enhanced by allosteric modulators. We have now investigated if brucine can enhance the inhibitory effects of muscarinic receptor agonists on the electrically evoked release of [3H]acetylcholine ([3H]ACh) from superfused slices of rat striatum. 2 The evoked release of [3H]ACh was inhibited by all agonists tested (i.e., furmethide, oxotremorine-M, bethanechol and oxotremorine). 3 Brucine enhanced the inhibitory effects of furmethide, oxotremorine-M and bethanechol on the evoked [3H]ACh release without altering the inhibitory effect of oxotremorine. 4 Alcuronium was applied for comparison and found to diminish the inhibitory effect of furmethide on the evoked [3H]ACh release. 5 The results demonstrate that it is possible both to enhance and diminish the functional effects of muscarinic receptor agonists by allosteric modulators. 6 The direction of the observed effects of brucine and Alcuronium on [3H]ACh release fully agrees with the effects of these modulators on the affinities of human M4 receptors for furmethide, oxotremorine-M, bethanechol and oxotremorine, as described by Jakubik et al. (1997). This supports the view that the presynaptic muscarinic receptors responsible for the autoinhibition of ACh release in rat striatum belong to the M4 muscarinic receptor subtype. British Journal of Pharmacology (1998) 124, 1213–1218; doi:10.1038/sj.bjp.0701966
O A Meretoja - One of the best experts on this subject based on the ideXlab platform.
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maintenance requirement of Alcuronium in paediatric patients
Anaesthesia and Intensive Care, 1990Co-Authors: O A Meretoja, T C K BrownAbstract:: 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.
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does suxamethonium influence the subsequent dose requirements of Alcuronium and its reversibility in children
Anaesthesia and Intensive Care, 1990Co-Authors: T C K Brown, O A Meretoja, D Clare, B BellAbstract:: 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.
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dose response of Alcuronium and d tubocurarine in infants children and adolescents
Anaesthesia and Intensive Care, 1990Co-Authors: O A Meretoja, T C K Brown, D ClareAbstract:: 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).
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postoperative neuromuscular block following atracurium or Alcuronium in children
Canadian Journal of Anaesthesia-journal Canadien D Anesthesie, 1990Co-Authors: O A Meretoja, Rowan GebertAbstract:Postoperative neuromuscular block (NMB) was evaluated in 60 children who received randomly either atracurium or Alcuronium to induce and maintain an 85–95 per cent NMB during balanced anaesthesia. The EMG-monitor was turned away from the anaesthetist 10–15 min before the end of surgery. The average NMB was comparable between the groups at the time of reversal with neostigmine 50 μg · kg−1 (84 ±9 per cent, mean ±SD) as were the NMB and the train-of-four ratio when the tracheas were extubated on a clinical basis (32 ±20 per cent and 50 ±18 per cent, respectively). Patients who had been paralyzed with atracurium arrived at the recovery room earlier and on arrival had greater train-of-four ratios than the patients paralyzed with Alcuronium (P 90 per cent was significantly shorter in the atracurium group (10 ±5 min vs 26 ±15 min, P < 0.001). Thus, an intermediate-acting muscle relaxant offers a safer recovery profile of the NMB than a long-acting muscle relaxant in paediatric patients.
Jan Jakubík - One of the best experts on this subject based on the ideXlab platform.
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protection by Alcuronium of muscarinic receptors against chemical inactivation and location of the allosteric binding site for Alcuronium
Journal of Neurochemistry, 2002Co-Authors: Jan Jakubík, Stanislav TucekAbstract:: 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.
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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, 1998Co-Authors: Jan Jakubík, Tatsuya Haga, Stanislav TucekAbstract: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.
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subtype selectivity of the positive allosteric action of Alcuronium at cloned m1 m5 muscarinic acetylcholine receptors
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Jan Jakubík, Lucie Bacakova, Esam E Elfakahany, Stanislav TucekAbstract: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.
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Positive allosteric interactions on cardiac muscarinic receptors: effects of chemical modifications of disulphide and carboxyl groups.
European Journal of Pharmacology, 1995Co-Authors: Jan Jakubík, Stanislav TucekAbstract:Abstract Changes in the allosteric effects of Alcuronium on rat cardiac muscarinic receptors were investigated after chemical modifications of S-S bonds or free carboxyl groups. In membranes pretreated with dithiothreitol, Alcuronium lost its positive action on the binding of [ 3 H ] methyl -N- scopolamine while its inhibitory effect on radioligand dissociation was preserved. In membranes pretreated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), known to modify free carboxyl groups in proteins, the ability to bind [ 3 H ] methyl -N- scopolamine was preserved if the pretreatment had been performed in the presence of Alcuronium, methyl-N-scopolamine or carbachol, while the positive cooperative effect of Alcuronium on [ 3 H ] methyl -N- scopolamine binding was only preserved in membranes that had been exposed to EDC in the presence of Alcuronium. Methyl-N-scopolamine, carbachol and Alcuronium differed in their ability to protect (against EDC) the action of Alcuronium on the rate of [ 3 H ] methyl -N- scopolamine dissociation. The results suggest that the disulphide bridge connecting the first two extracellular loops of muscarinic receptors is important for the positive allosteric action of Alcuronium and that three carboxyl groups (presumably aspartate residues) are involved in receptor interactions with Alcuronium and methyl-N-scopolamine. The first group is important for the effect of Alcuronium on the affinity for methyl-N-scopolamine, the second is critical for the effect of Alcuronium on the rate of methyl-N-scopolamine dissociation, and the third is critical for methyl-N-scopolamine binding. Presumably, the two charged nitrogens of Alcuronium associate with the first and the second of the three groups involved.
Klaus Mohr - One of the best experts on this subject based on the ideXlab platform.
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allosteric modulation of muscarinic receptor signaling Alcuronium induced conversion of pilocarpine from an agonist into an antagonist
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Katrin Zahn, Niels Eckstein, Christian Trankle, Wolfgang Sadee, Klaus MohrAbstract:Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent Alcuronium is known to bind with similar affinity to the M2 subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by Alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M2-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC50, Alc = 5.63) without any effect on the EC50 of pilocarpine, consistent with an allosteric mechanism. In contrast, Alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (p K A, Alc = 5.54). If pilocarpine remained receptor bound in the presence of Alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 μM Alcuronium. Measuring guanosine 5′- O -(3-[35S]thio)triphosphate ([35S]GTPγS) binding in CHO-M2 membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [35S]GTPγS binding (pIC50, Alc = 5.47) without shift in EC50, whereas it competitively shifted the response to oxotremorine M (p K A, Alc = 5.97). [3H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, Alcuronium converted the agonist pilocarpine into an antagonist—a novel type of functional allosteric interaction.
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Testing the specificity of allosteric modulators of muscarinic receptors in phylogenetically closely related histamine H1-receptors.
Naunyn-schmiedebergs Archives of Pharmacology, 2000Co-Authors: C. Franken, Christian Trankle, Klaus MohrAbstract:Gallamine, Alcuronium and W84 (hexane-1,6-bis[dimethyl-3'-phthalimidopropyl-ammonium bromide]) are prototype allosteric modulators of the G-protein coupled muscarinic acetylcholine receptor family, especially of the M2-subtype. In order to probe the specificity of muscarinic allosteric modulation, we checked whether these agents interact with histamine H1-receptors which have a high homology with muscarinic receptors. Binding experiments (38 mM Na2HPO4, 12 mM KH2PO4, pH 7.5) were performed with the H1-receptor antagonist [3H]mepyramine ([3H]MEP) in guinea pig cerebellar homogenates. For the sake of comparison, binding of [3H]N-methylscopolamine ([3H]NMS) at muscarinic M2-receptors was measured in porcine cardiac homogenates under identical conditions. The modulators retarded [3H]NMS dissociation (t 1/2,control=1.3 min) concentration-dependently indicating their allosteric action with half-maximum effects for gallamine at EC50,diss=27 µM, for Alcuronium at EC50,diss=53 nM, and for W84 at EC50,diss=170 nM. In contrast, [3H]MEP dissociation from H1-receptors (t 1/2,control=2.6 min) remained unchanged up to concentrations of 1 mM of the modulators. Equilibrium binding of [3H]NMS (K D=0.46 nM, B max=98 fmol/mg protein) was inhibited by gallamine, elevated by Alcuronium and left almost unchanged by W84, indicating negative, positive and nearly neutral cooperativity, respectively, with the radioligand. The ternary complex model of allosteric actions yielded the equilibrium dissociation constants K A for the binding of the allosteric modulators to free M2-receptors: K A,gallamine=100 nM, K A,Alcuronium=450 nM, K A,W84=69 nM. In H1-receptors, more than 1000-fold higher concentrations than in M2-receptors were required to elicit an effect on the binding of [3H]MEP (K D=1.2 nM, B max=205 fmol/mg protein). Half-maximal reduction was observed at 10 mM for gallamine, 1 mM for Alcuronium and 92 µM for W84. In conclusion, the muscarinic modulators have little effect on the histamine H1-receptors.
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opposite effects of Alcuronium on agonist and on antagonist binding to muscarinic receptors
European Journal of Pharmacology, 1996Co-Authors: Andrea Maas, Klaus MohrAbstract:Abstract Alcuronium is known to retard allosterically the dissociation of [3H]N-methylscopolamine from muscarinic M2 receptors, thereby augmenting the binding of this antagonist. Functionally, Alcuronium behaves as a weak antimuscarinic agent and induces in combination with N-methylscopolamine an overadditive antimuscarinic action with oxotremorine-M as the agonist. The effect of Alcuronium on the binding of [3H]oxotremorine-M was studied in porcine heart homogenates. Agonist binding was concentration dependently inhibited with a Ki = 0.48 ± 0.03 μM (means ± S.D., n = 3). Under identical conditions [3H]N-methylscopolamine binding was elevated. Alcuronium, 100 μM, which nearly prevented the dissociation of [3H]N-methylscopolamine, retarded the rate of dissociation of [3H]oxotremorine-M only by a factor of two. These findings support the notion that the overadditive antimuscarinic action of Alcuronium in conjunction with N-methylscopolamine is based on a shift by Alcuronium of the interplay between agonist and antagonist in favour of the antagonist.
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potentiation by Alcuronium of the antimuscarinic effect of n methylscopolamine in guinea pig left atria
European Journal of Pharmacology, 1995Co-Authors: Andrea Maas, Evi Kostenis, Klaus MohrAbstract:Abstract Alcuronium is known to stabilize allosterically the binding of the muscarinic antagonist N-methylscopolamine to muscarinic M2 receptors and thus to elevate the equilibrium binding of N-methylscopolamine in homogenized cardiac tissue. In order to check for a functional consequence of this effect, the action of Alcuronium alone and in combination with N-methylscopolamine was determined in contracting guinea pig left auricles with oxotremorine-M as the negative inotropic agonist. For sake of comparison, the allosteric modulator W84 = hexane-1,6-bis(dimethyl-3′-phthalimidopropyl-ammonium bromide) was included. Alcuronium displayed a weak antimuscarinic action (pA2 = 5.7). In conjunction with 10−7 M N-methylscopolamine, Alcuronium (≥ 10−6 M) induced a more pronounced antimuscarinic effect than expected for a combination of competitive antagonists. The extent of overadditivity with combinations of W84 and 10−7 M N-methylscopolamine was smaller. In conclusion, Alcuronium potentiates the antimuscarinic effect of N-methylscopolamine in contracting cardiac preparations with high effectivity.
Rowan Gebert - One of the best experts on this subject based on the ideXlab platform.
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postoperative neuromuscular block following atracurium or Alcuronium in children
Canadian Journal of Anaesthesia-journal Canadien D Anesthesie, 1990Co-Authors: O A Meretoja, Rowan GebertAbstract:Postoperative neuromuscular block (NMB) was evaluated in 60 children who received randomly either atracurium or Alcuronium to induce and maintain an 85–95 per cent NMB during balanced anaesthesia. The EMG-monitor was turned away from the anaesthetist 10–15 min before the end of surgery. The average NMB was comparable between the groups at the time of reversal with neostigmine 50 μg · kg−1 (84 ±9 per cent, mean ±SD) as were the NMB and the train-of-four ratio when the tracheas were extubated on a clinical basis (32 ±20 per cent and 50 ±18 per cent, respectively). Patients who had been paralyzed with atracurium arrived at the recovery room earlier and on arrival had greater train-of-four ratios than the patients paralyzed with Alcuronium (P 90 per cent was significantly shorter in the atracurium group (10 ±5 min vs 26 ±15 min, P < 0.001). Thus, an intermediate-acting muscle relaxant offers a safer recovery profile of the NMB than a long-acting muscle relaxant in paediatric patients.