Disease relevance of Lopac-M-105

• Further, the attenuated relaxation to isoproterenol and PGE2 was ablated in the IL-1beta-treated TSM that were pretreated with either the muscarinic M2-receptor antagonist, methoctramine (10(-6) M), or pertussis toxin (100 ng/ml) [1].
• Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia [2].
• Thus, 1-naphthylacetylspermine and N,N'-bis[6-[[(2-methoxyphenyl)methyl]amino]hexyl]-1,8-octanediamine (methoctramine) were especially effective in increasing the permeability of the outer membrane of E. coli cells, being comparable to polymyxin B nonapeptide, a well-known cationic peptide showing such action [3].
• The nonspecific muscarinic antagonist scopolamine and the M1 muscarinic receptor antagonist pirenzepine, but neither the M2 muscarinic antagonist methoctramine nor the nicotinic antagonist hexamethonium, attenuated bradycardia [4].
• Finally, in the pithed rat, methoctramine preferentially inhibited cardiac M2 (vagal bradycardia) over ganglionic M1 (McN-A-343-induced hypertension) responses [5].

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

• In contrast, methoctramine, pertussis toxin (PTx), or Galphai3 antibody converted the decrease in cAMP to increase above basal level (+28 +/- 5 to +32 +/- 6%); the increase in cAMP was abolished by 4-DAMP or Gbeta antibody [14].
• The M2 selective antagonist methoctramine (3.16 microM) produced a 307-fold increase in the ED50 for bradycardia but had no significant effect on the pressor response to acetylcholine [15].
• The muscarinic M2 antagonist, methoctramine (7-240 nmol kg-1), inhibited the bradycardia induced by both vagal stimulation and ACh (ED50: 38 +/- 5 and 38 +/- 9 nmol kg-1, respectively) [16].
• Experiments designed to gain insight into the muscarinic receptor subtypes mediating REM sleep enhancement involved pontine reticular formation administration of neostigmine after pertussis toxin, neostigmine after methoctramine, and neostigmine after pirenzepine [17].
• Histamine release and inositol phosphates generation induced by methoctramine were both inhibited by pertussis toxin pretreatment [18].

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

• 4-DAMP and methoctramine increased 3H overflow from [3H]choline-labelled strips in response to electrical stimulation, contrary to pirenzepine, which decreased the overflow [37].
• This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to altered arachidonic acid metabolism or beta-adrenergic antagonism [38].
• This study assessed changes in extracellular ACh levels, via in vivo microdialysis, following administration of the m2 antagonist methoctramine [39].
• Arecaidine propargyl ester (APE), an M2 agonist, produced coronary artery constriction which was attenuated by methoctramine (0.1 microM) but not by pirenzepine (0.1 microM) in both spontaneously beating and KCl-arrested hearts [40].
• 2. Intravenous injection of methoctramine, atropine, pirenzepine (an M1-selective muscarinic antagonist) or 4-DAMP (an M3-selective muscarinic antagonist) each significantly increased heart rate in comparison to vehicle controls [41].

References