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Chemical Compound Review

Flaxedil     2-[2,6-bis(2- triethylammonioethoxy) phenoxy...

Synonyms: Gallamine-3ETI, S2471_Selleck, AG-G-45691, CCG-40105, HSDB 3229, ...
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Disease relevance of gallamine

  • In 14 of our patients, the time course of gallamine concentrations in the plasma before, during, and after CPB was similar to that in normal surgical patients, indicating little or no effect of cardiac disease or CPB [1].
  • The antagonistic effects of gallamine on muscarinic receptor-linked responses were investigated in N1E-115 neuroblastoma cells [2].
  • Vagally-induced bradycardia was abolished by gallamine, confirming antagonism of the effect of acetylcholine on muscarinic receptors in the heart [3].
  • However, gallamine, while an effective antagonist of M2 responses, also has the ability to modify the electrical characteristics of ganglion cells and thus may modify ganglionic transmission by mechanisms other than antagonism of receptors [4].
  • 5. The difference between A- and C-fibers could not be accounted for on the basis of the maturity of the neuroma, rate and pattern of ongoing discharge, or use of Flaxedil paralysis [5].

Psychiatry related information on gallamine

  • Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine [6].
  • The increase in cataplexy in narcoleptic canines produced by local perfusion with carbachol (10(-4) M) followed by equimolar perfusion with a muscarinic antagonist was rapidly reversed by atropine (muscarinic) and gallamine (M2 muscarinic), partially reversed by 4-DAMP (M3/M1 muscarinic) and completely unaffected by pirenzepine (M1 muscarinic) [7].
  • Pirenzepine, an inhibitor of M1 muscarinic receptors, was effective in producing amnesia, whereas gallamine, an M2 receptor inhibitor, did not produce amnesia [8].
  • Electrographic variables for determining the states of sleep and wakefulness, the electrocorticogram, lateral geniculate nucleus potentials, and dorsal hippocampal potentials, were recorded before, during and after the administration of gallamine triethiodide to cats with chronically implanted electrodes [9].
  • In conscious Wistar rats neuromuscularly paralysed by gallamine, operantly conditioned reduction of heart rate was achieved under both negative and positive reinforcement schedules using the tail shock avoidance or the rewarding brain-stimulations in 20-min test sessions [10].

High impact information on gallamine

  • Voltage-clamp studies show that gallamine also directly affects amphibian and mammalian myelinated nerve fibers [11].
  • In controls, blockade of neuronal M2 muscarinic receptors by gallamine potentiated vagally induced bronchoconstriction, while in challenged animals this effect was markedly reduced, confirming M2 receptor dysfunction [12].
  • The pressor and sympathoexcitatory effects of ouabain in the RVLM were reversed by microinjections of an M2 muscarinic antagonist, gallamine, or digoxin-specific antibody Fab fragments [13].
  • To characterize central integration of reflex responses to stimulation of mechanically and chemically sensitive receptors in the heart and lung, male rats (350 to 425 g) were anesthetized (pentobarbital, 50 mg/kg IP) and paralyzed (gallamine triethiodide, 25 mg/kg IV) and then they underwent bilateral sinoaortic denervation [14].
  • These changes in SP-LI, mean arterial pressure, and heart rate were virtually abolished when the contractions were repeated after sectioning the L-5-S-2 dorsal and ventral roots or when the electrical stimulation of the ventral roots was repeated after muscle paralysis with gallamine triethiodide [15].

Chemical compound and disease context of gallamine


Biological context of gallamine

  • We interpret our data to suggest that gallamine not only competes for [3H]QNB binding sites, but also binds at a secondary site on the receptor, forming a ternary complex with [3H]QNB [21].
  • The results suggest that the allosteric site for gallamine binding in the m2 receptor residues at or near the putative third outer domain and that both the EDGE motif and Asp-97 play an essential role in the interaction between the two sites [22].
  • For the receptors studied, a good agreement was found between the alpha KdA values calculated from the Schild analysis and the IC50 values for the effect of gallamine on the N-methylscopolamine off-rate [22].
  • The two main methods used were (i) Schild analysis of equilibrium binding data and (ii) study of the effect of gallamine on the dissociation kinetics of N-methylscopolamine [22].
  • All five (m1-m5) muscarinic receptors are sensitive to allosteric regulation, but gallamine is considerably more potent in slowing the dissociation of N-[3H]methylscopolamine (NMS) from the m2 subtype than from the m3 or m5 subtypes [23].

Anatomical context of gallamine

  • These results suggest that dopamine plays a prominent role in mediating the stimulatory effects of d-AMP on the firing rates of a population of globus pallidus cells in gallamine-paralyzed rats [24].
  • To this end, the effects of the M2-selective muscarinic receptor antagonists AQ-RA 741 and gallamine were studied on electrical field stimulation-induced twitch contractions of preparations from trachea and from bronchial airways of varying diameter [25].
  • Similar results were obtained with muscarinic receptors from the brainstem, but gallamine had only marginal effects on the dissociation of [3H]QNB in the forebrain [26].
  • We examined changes in the binding of [3H]NMS to membranes of rat heart atria exposed to various concentrations of a positive allosteric effector (alcuronium or strychnine) and of a negative allosteric effector (gallamine) simultaneously [27].
  • Furthermore, AC-42 and gallamine significantly retarded the rate of [(3)H]NMS dissociation from CHO-hM(1) cell membranes, conclusively demonstrating their ability to bind to a topographically distinct site to change M(1) receptor conformation [28].

Associations of gallamine with other chemical compounds


Gene context of gallamine

  • 2. Atropine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a muscarinic M3 antagonist), pirenzepine (a muscarinic M1 antagonist), methoctramine and gallamine (muscarinic M2 antagonists) inhibited the acetylcholine-induced Ca2+ release, with a high affinity for 4-DAMP and atropine and a low affinity for the other antagonists [32].
  • The M(1) muscarinic antagonist pirenzepine, the M(2) muscarinic antagonist gallamine, and the M(1)/M(3) muscarinic receptor antagonist N-(3-chloropropyl)-4-piperidinyl diphenylacetate (4-DAMP) also inhibited carbachol-stimulated MAPK activation [33].
  • By comparison, gallamine was four- to fivefold less potent in blocking noncardiac M2 muscarinic receptor-mediated inhibition of cyclic AMP formation, with a Ki value of 144 microM [2].
  • The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA [34].
  • When CB1 receptors were not blocked, oxo-M suppressed IPSCs in a gallamine-resistant manner in cannabinoid-sensitive pairs [35].

Analytical, diagnostic and therapeutic context of gallamine


  1. Gallamine disposition in open-heart surgery involving cardiopulmonary bypass. Shanks, C.A., Ramzan, I.M., Walker, J.S., Brown, K.F. Clin. Pharmacol. Ther. (1983) [Pubmed]
  2. Mixed competitive and allosteric antagonism by gallamine of muscarinic receptor-mediated second messenger responses in N1E-115 neuroblastoma cells. Lee, N.H., el-Fakahany, E.E. J. Neurochem. (1989) [Pubmed]
  3. Muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea-pig. Fryer, A.D., Maclagan, J. Br. J. Pharmacol. (1984) [Pubmed]
  4. Differential effects of the muscarinic M2 antagonists, AF-DX 116 and gallamine, on single neurons of rabbit sympathetic ganglia. Yarosh, C.A., Ashe, J.H., Olito, A.C. Neuropharmacology (1990) [Pubmed]
  5. Axonal cross-excitation in nerve-end neuromas: comparison of A- and C-fibers. Amir, R., Devor, M. J. Neurophysiol. (1992) [Pubmed]
  6. Pain responses to perineuromal injection of normal saline, gallamine, and lidocaine in humans. Chabal, C., Jacobson, L., Russell, L.C., Burchiel, K.J. Pain (1989) [Pubmed]
  7. Cholinergic regulation of cataplexy in canine narcolepsy in the pontine reticular formation is mediated by M2 muscarinic receptors. Reid, M.S., Tafti, M., Nishino, S., Siegel, J.M., Dement, W.C., Mignot, E. Sleep. (1994) [Pubmed]
  8. Cholinergic receptor antagonists impair formation of intermediate-term memory in the chick. Patterson, T.A., Lipton, J.R., Bennett, E.L., Rosenzweig, M.R. Behavioral and neural biology. (1990) [Pubmed]
  9. Sleep during neuromuscular blockade in cats. Glenn, L.L., Foutz, A.S., Dement, W.C. Electroencephalography and clinical neurophysiology. (1980) [Pubmed]
  10. Success of autonomic operant conditioning of heart rate without involving contractions of somatic skeletal muscles. Bindu, P.N., Desiraju, T. Indian J. Physiol. Pharmacol. (1988) [Pubmed]
  11. Gallamine triethiodide (flaxedil): tetraethylammonium- and pancuronium-like effects in myelinated nerve fibers. Smith, K.J., Schauf, C.L. Science (1981) [Pubmed]
  12. Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways. Fryer, A.D., Costello, R.W., Yost, B.L., Lobb, R.R., Tedder, T.F., Steeber, D.A., Bochner, B.S. J. Clin. Invest. (1997) [Pubmed]
  13. Role of ouabain-like compound in the rostral ventrolateral medulla in rats. Teruya, H., Yamazato, M., Muratani, H., Sakima, A., Takishita, S., Terano, Y., Fukiyama, K. J. Clin. Invest. (1997) [Pubmed]
  14. Responses of neurons in the nucleus tractus solitarius to stimulation of heart and lung receptors in the rat. Hines, T., Toney, G.M., Mifflin, S.W. Circ. Res. (1994) [Pubmed]
  15. Effects of graded muscle contractions on spinal cord substance P release, arterial blood pressure, and heart rate. Wilson, L.B., Fuchs, I.E., Mitchell, J.H. Circ. Res. (1993) [Pubmed]
  16. A vagolytic action of neuromuscular blocking agents at the pacemaker of the isolated guinea pig atrium. Son, S.L., Waud, D.R. Anesthesiology (1978) [Pubmed]
  17. Neuromuscular relaxants as antagonists for M2 and M3 muscarinic receptors. Hou, V.Y., Hirshman, C.A., Emala, C.W. Anesthesiology (1998) [Pubmed]
  18. A comparison of intraosseous and intravenous routes of administration for antiseizure agents. Lathers, C.M., Jim, K.F., Spivey, W.H. Epilepsia (1989) [Pubmed]
  19. Inhibitory M2 muscarinic receptors are upregulated in both axotomized and intact small diameter dorsal root ganglion cells after peripheral nerve injury. Hayashida, K.I., Bynum, T., Vincler, M., Eisenach, J.C. Neuroscience (2006) [Pubmed]
  20. Comparison of gallamine with d-tubocurarine effects on fasciculations after succinylcholine. Virtue, R.W. Anesth. Analg. (1975) [Pubmed]
  21. Heterogeneity of binding sites on cardiac muscarinic receptors induced by the neuromuscular blocking agents gallamine and pancuronium. Dunlap, J., Brown, J.H. Mol. Pharmacol. (1983) [Pubmed]
  22. Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the m2 muscarinic acetylcholine receptor. Leppik, R.A., Miller, R.C., Eck, M., Paquet, J.L. Mol. Pharmacol. (1994) [Pubmed]
  23. Use of chimeric muscarinic receptors to investigate epitopes involved in allosteric interactions. Ellis, J., Seidenberg, M., Brann, M.R. Mol. Pharmacol. (1993) [Pubmed]
  24. Neuronal responses of the globus pallidus to systemic administration of d-amphetamine: investigation of the involvement of dopamine, norepinephrine, and serotonin. Bergstrom, D.A., Walters, J.R. J. Neurosci. (1981) [Pubmed]
  25. Muscarinic inhibitory autoreceptors in different generations of human airways. ten Berge, R.E., Zaagsma, J., Roffel, A.F. Am. J. Respir. Crit. Care Med. (1996) [Pubmed]
  26. Gallamine exerts biphasic allosteric effects at muscarinic receptors. Ellis, J., Seidenberg, M. Mol. Pharmacol. (1989) [Pubmed]
  27. Competition between positive and negative allosteric effectors on muscarinic receptors. Proska, J., Tucek, S. Mol. Pharmacol. (1995) [Pubmed]
  28. Probing the molecular mechanism of interaction between 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42) and the muscarinic M(1) receptor: direct pharmacological evidence that AC-42 is an allosteric agonist. Langmead, C.J., Fry, V.A., Forbes, I.T., Branch, C.L., Christopoulos, A., Wood, M.D., Herdon, H.J. Mol. Pharmacol. (2006) [Pubmed]
  29. Comparable 30-kDa apamin binding polypeptides may fulfill equivalent roles within putative subtypes of small conductance Ca(2+)-activated K+ channels. Wadsworth, J.D., Doorty, K.B., Strong, P.N. J. Biol. Chem. (1994) [Pubmed]
  30. Effects of edrophonium, eserine, decamethonium, d-tubocurarine, and gallamine on the kinetics of membrane-bound and solubilized eel acetylcholinesterase. Robaire, B., Kato, G. Mol. Pharmacol. (1975) [Pubmed]
  31. Probing of the location of the allosteric site on m1 muscarinic receptors by site-directed mutagenesis. Matsui, H., Lazareno, S., Birdsall, N.J. Mol. Pharmacol. (1995) [Pubmed]
  32. Specific Gq protein involvement in muscarinic M3 receptor-induced phosphatidylinositol hydrolysis and Ca2+ release in mouse duodenal myocytes. Morel, J.L., Macrez, N., Mironneau, J. Br. J. Pharmacol. (1997) [Pubmed]
  33. Cholinergic agonists transactivate EGFR and stimulate MAPK to induce goblet cell secretion. Kanno, H., Horikawa, Y., Hodges, R.R., Zoukhri, D., Shatos, M.A., Rios, J.D., Dartt, D.A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  34. Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease. Costagli, C., Galli, A. Biochem. Pharmacol. (1998) [Pubmed]
  35. Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. Fukudome, Y., Ohno-Shosaku, T., Matsui, M., Omori, Y., Fukaya, M., Tsubokawa, H., Taketo, M.M., Watanabe, M., Manabe, T., Kano, M. Eur. J. Neurosci. (2004) [Pubmed]
  36. Expression of soluble ligand- and antibody-binding extracellular domain of human muscle acetylcholine receptor alpha subunit in yeast Pichia pastoris. Role of glycosylation in alpha-bungarotoxin binding. Psaridi-Linardaki, L., Mamalaki, A., Remoundos, M., Tzartos, S.J. J. Biol. Chem. (2002) [Pubmed]
  37. Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-{alpha}-deficient Mice. Carey, M.A., Card, J.W., Bradbury, J.A., Moorman, M.P., Haykal-Coates, N., Gavett, S.H., Graves, J.P., Walker, V.R., Flake, G.P., Voltz, J.W., Zhu, D., Jacobs, E.R., Dakhama, A., Larsen, G.L., Loader, J.E., Gelfand, E.W., Germolec, D.R., Korach, K.S., Zeldin, D.C. Am. J. Respir. Crit. Care Med. (2007) [Pubmed]
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