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Chemical Compound Review

Methoctramine     N,N'-bis[6-[(2- methoxyphenyl)methylamino]h...

Synonyms: CHEMBL500996, M105_SIGMA, CHEBI:73452, CHEBI:567251, M-105, ...
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Disease relevance of Lopac-M-105


Psychiatry related information on Lopac-M-105

  • The ID50 ratio for methoctramine-to-4-DAMP (3.0) was similar to the affinity ratio of methoctramine-to-4-DAMP only at the M2 subtype (3.5), suggesting that the M2 subtype in the mPRF modulates the amount of REM sleep [6].
  • The present data suggests that the decrease in activation of inhibitory muscarinic M2 autoreceptors induced by methoctramine produces a specific improvement of short-term memory at long forgetting delays [7].
  • The effects of methoctramine, a cardioselective muscarinic cholinergic antagonist, on heart rate and small intestinal motor activity were compared to those of the nonselective competitive muscarinic antagonist, atropine [8].
  • Administration of muscarinic M(1) agonist McN-A-343 reversed the memory deficit observed in TD mice, although the muscarinic M(2) antagonist methoctramine did not [9].

High impact information on Lopac-M-105

  • Data are presented which suggest that methoctramine might interact with four acidic residues of the receptor: two residues are buried in the third transmembrane segment whereas the others are located extracellularly on the loop 4-5 which may represent the allosteric site where several antagonists such as gallamine bind [10].
  • Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability [2].
  • RESULTS: In isolated circular smooth muscle cells, challenged with ACh, the muscarinic 3 receptor (M3R) antagonists 4-DAMP and pF-HSD each showed a 50% decrease in antagonism on D4 while the M2R antagonist methoctramine more than doubled its potency, showing a decreased role of M3R and an increased role of M2R, respectively [11].
  • In ACh release studies, the M3 antagonist had no significant effect, whereas pirenzepine, methoctramine, and rispenzepine significantly increased ACh release in guinea pig trachea [12].
  • The M3 subtype (typically found in rat pancreas, a tissue expressing the m3 mRNA) had a low affinity for himbacine and methoctramine and represented about 10% of all [3H]NMS receptors in rat brain cortex, hippocampus, striatum, and cerebellum [13].

Chemical compound and disease context of Lopac-M-105


Biological context of Lopac-M-105

  • In radioligand binding experiments, methoctramine and AF-DX 116 competed for approximately 85% of the 3H-quinuclidynyl benzilate (3H-QNB) binding sites on intact cells with high affinities (-log KI of 7.73 +/- 0.16 and 6.67 +/- 0.31, respectively) characteristic of binding to M2 receptors [19].
  • The M3 antagonist p-fluorohexahydrosiladifenidol (IC50 = 0.5-0.8 microM) inhibited the increases in [Ca2+]i, IP3, and cAMP more effectively than the M1 antagonist pirenzepine (IC50 = 5-9 microM) and the M2 antagonist methoctramine (IC50 = 20-30 microM) [20].
  • Structure-activity relationships of methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists. 3. Effect of inserting the tetraamine backbone into a macrocyclic structure [21].
  • Competitive binding studies revealed high- and low-affinity binding sites for the receptor antagonists, pirenzepine, methoctramine and the p-fluoro analog of hexahydro-sila-difenidol (p-F-HHSiD) [22].
  • Methoctramine binding sites sensitive to alkylation on muscarinic receptors from tracheal smooth muscle [23].

Anatomical context of Lopac-M-105

  • One M4 subtype had a high affinity for himbacine and methoctramine; it was found predominantly in homogenates from rat striatum (46% of total [3H]NMS receptors) and in lower proportion in cortex (33% of [3H]NMS receptors) and hippocampus (16% of [3H]NMS receptors) [13].
  • Several polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blocking activity on M-2 muscarinic receptors in guinea pig atria and ileum [24].
  • 3. Perfusion of the neuromuscular junction with methoctramine, a selective M(2)/M(4) muscarinic antagonist, increased the quantal content and slowed the exponential decay of the synaptic delay histograms [25].
  • Both these ligands, owing to their improved lipophilicity relative to tripitramine and methoctramine, could serve as tools in investigating cholinergic functions in the central nervous system [26].
  • The presynaptic muscarinic autoreceptor of Torpedo marmorata electric organ has been characterised by radioligand binding studies using the subtype-selective antagonists pirenzepine, (+)-telenzepine, methoctramine, and AF-DX 116 [27].

Associations of Lopac-M-105 with other chemical compounds

  • 3. The neutral muscarinic antagonists, AF-DX 116 and atropine, did not modify the inhibitory effect of high concentrations of methoctramine, indicating that this effect was not related to the antagonist binding site of muscarinic receptors [28].
  • Pirenzepine was found to be nonspecific in blocking the carbachol-stimulated hydrolysis of PI and inhibition of adenylate cyclase, while methoctramine specifically antagonized carbachol-stimulated inhibition of adenylate cyclase with 600 times greater potency than carbachol-stimulated hydrolysis of PI [29].
  • Intrathecal administration of 50 nmol of idazoxan, 100 nmol of S-(-)-propranolol, 20 nmol of LY53857, 25 nmol of S-(-)-zacopride, 100 nmol of pirenzepine or 50 nmol of methoctramine each antagonized in part the antinociception produced by PPTg or RMg microinjections of 40 nmol of NMC [30].
  • 1. The effects of spermine and methoctramine, a selective M2 muscarinic receptor antagonist, were studied on the high-affinity GTPase activity of G proteins, and on ligand binding to M2 muscarinic receptors in pig heart sarcolemma [28].
  • The present study examined the ability of the M2/M4 muscarinic ACh receptor antagonist N,N'-bis [6-[[(2-methoxyphenyl)methyl]amino]hexyl]-1,8-octane diamine tetrahydrochloride (methoctramine) to induce and modulate synaptic plasticity in the CA1 area of the hippocampus in urethane-anesthetized rats [31].

Gene context of Lopac-M-105

  • This response was completely blocked by preincubating TMps with pirenzepine and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), M1 and M3 receptor antagonists, and partly by the M2 receptor antagonist methoctramine [32].
  • By contrast, an M2 receptor antagonist, methoctramine tetrahydrochloride (10 microM), was ineffective [33].
  • These seizures could be inhibited by coinjection of methoctramine with the M1-specific antagonist, pirenzepine [34].
  • Methoctramine + AChE occluded the prepulse effects [35].
  • Antagonism of M2, M3 and M4 muscarinic receptor effects with methoctramine (3-100 nM), rho-FHHSiD (3-30 nM) or MT-3 (10-300 nM) did not significantly affect the inhibitory action of ACh on GLP-1 stimulated cAMP production [36].

Analytical, diagnostic and therapeutic context of Lopac-M-105


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  8. Effects of a selective and a nonselective muscarinic cholinergic antagonist on heart rate and intestinal motility in dogs. Hendrix, P.K., Robinson, E.P. J. Vet. Pharmacol. Ther. (1997) [Pubmed]
  9. Behavioral and neurochemical alterations following thiamine deficiency in rodents: relationship to functions of cholinergic neurons. Nakagawasai, O. Yakugaku Zasshi (2005) [Pubmed]
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  11. Divergent changes to muscarinic and serotonergic signalling following colitis. Wells, R.W., Blennerhassett, M.G. Gut (2005) [Pubmed]
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  14. Differential coupling of muscarinic m2 and m3 receptors to adenylyl cyclases V/VI in smooth muscle. Concurrent M2-mediated inhibition via Galphai3 and m3-mediated stimulation via Gbetagammaq. Murthy, K.S., Makhlouf, G.M. J. Biol. Chem. (1997) [Pubmed]
  15. Differentiation of muscarinic receptors mediating negative chronotropic and vasoconstrictor responses to acetylcholine in isolated rat hearts. Hoover, D.B., Neely, D.A. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  16. Actions of methoctramine, a muscarinic M2 receptor antagonist, on muscarinic and nicotinic cholinoceptors in guinea-pig airways in vivo and in vitro. Watson, N., Barnes, P.J., Maclagan, J. Br. J. Pharmacol. (1992) [Pubmed]
  17. M2 muscarinic receptors in pontine reticular formation of C57BL/6J mouse contribute to rapid eye movement sleep generation. Coleman, C.G., Lydic, R., Baghdoyan, H.A. Neuroscience (2004) [Pubmed]
  18. The M2 muscarinic receptor antagonist methoctramine activates mast cells via pertussis toxin-sensitive G proteins. Chahdi, A., Daeffler, L., Bueb, J.L., Gies, J.P., Landry, Y. Naunyn Schmiedebergs Arch. Pharmacol. (1998) [Pubmed]
  19. Muscarinic regulation of cyclic AMP in bovine trachealis cells. Schaefer, O.P., Ethier, M.F., Madison, J.M. Am. J. Respir. Cell Mol. Biol. (1995) [Pubmed]
  20. Stimulation of adenylyl cyclase mediated by phospholipase C-linked M3 muscarinic receptor in human neuroblastoma SK-N-BE (2) C cells. Suh, B.C., Kim, K.T. J. Neurochem. (1995) [Pubmed]
  21. Structure-activity relationships of methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists. 3. Effect of inserting the tetraamine backbone into a macrocyclic structure. Bolognesi, M.L., Bixel, M.G., Marucci, G., Bartolini, M., Krauss, M., Angeli, P., Antonello, A., Rosini, M., Tumiatti, V., Hucho, F., Melchiorre, C. J. Med. Chem. (2002) [Pubmed]
  22. Differential effects of alkylating agents on the multiple muscarinic receptor subtypes linked to activation of phospholipase C by carbachol in rat brain cortical membranes. Sallés, J., Wallace, M.A., Fain, J.N. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  23. Methoctramine binding sites sensitive to alkylation on muscarinic receptors from tracheal smooth muscle. Misle, A.J., Lippo de Bécemberg, I., González de Alfonzo, R., Alfonzo, M.J. Biochem. Pharmacol. (1994) [Pubmed]
  24. Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M-2 muscarinic receptor blocking activity. Melchiorre, C., Quaglia, W., Picchio, M.T., Giardinà, D., Brasili, L., Angeli, P. J. Med. Chem. (1989) [Pubmed]
  25. Presynaptic M(2) muscarinic receptors are involved in controlling the kinetics of ACh release at the frog neuromuscular junction. Slutsky, I., Silman, I., Parnas, I., Parnas, H. J. Physiol. (Lond.) (2001) [Pubmed]
  26. Universal template approach to drug design: polyamines as selective muscarinic receptor antagonists. Bolognesi, M.L., Minarini, A., Budriesi, R., Cacciaguerra, S., Chiarini, A., Spampinato, S., Tumiatti, V., Melchiorre, C. J. Med. Chem. (1998) [Pubmed]
  27. Muscarinic autoreceptors of Torpedo electric organ are of the M1 subtype: evidence by radioligand binding using selective antagonists. Green, A.C., Dowdall, M.J. J. Neurochem. (1992) [Pubmed]
  28. Inhibition of GTPase activity of Gi proteins and decreased agonist affinity at M2 muscarinic acetylcholine receptors by spermine and methoctramine. Daeffler, L., Chahdi, A., Gies, J.P., Landry, Y. Br. J. Pharmacol. (1999) [Pubmed]
  29. Specificity of methoctramine in blocking muscarinic receptors which inhibit adenylate cyclase in cerebellar granule cells. McLeskey, S.W., Fischofer-Hahn, C., Takahashi, K., Wojcik, W.J. Neuropharmacology (1990) [Pubmed]
  30. Adrenergic, serotonergic and cholinergic components of nicotinic antinociception in rats. Iwamoto, E.T., Marion, L. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
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