Disease relevance of mecamylamine

• Pancreatitis was preceded by unilateral left cervical vagotomy or pretreatment with the nicotinic receptor antagonist mecamylamine or by pretreatment with the selective alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21) [1].
• RESULTS: Vagotomy or pretreatment with mecamylamine resulted in an enhanced severity of pancreatitis, as reflected by histology, edema, plasma hydrolases, and interleukin-6 levels [1].
• Pre-treatment of animals with the ganglion blocker mecamylamine (3 mg.kg-1 s.c.) reduced the pressor effect of amylin [2].
• Administration of the C6-type nicotinic antagonist mecamylamine not only countered the smoking effect, but ameliorated the spontaneous positive and negative myoclonus [3].
• PGE1 hyperthermia was significantly reduced by microinjections of the muscarinic and nicotinic antagonists, atropine, or mecamylamine, at PGE1 reactive sites in the AH/POA [4].

Psychiatry related information on mecamylamine

• Treatment of Tourette's syndrome with mecamylamine [5].
• In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder [6].
• The higher dose of mecamylamine (3.0 mg/kg) also interfered with motor activity and it decreased the choice accuracy [7].
• Mecamylamine treatment began 2 weeks before smoking cessation [8].
• Although mecamylamine significantly elevated tail temperature by more than 2 degrees C, it failed to alter response latencies [9].

High impact information on mecamylamine

• Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway [10].
• H82 cell proliferation was also inhibited by the muscarinic and nicotinic antagonists atropine and mecamylamine, respectively, in dose- and time-dependent manners [11].
• Expression in Xenopus oocytes of combinations of these subunits that include the unc-38 alpha subunit results in levamisole-induced currents that are suppressed by the nAChR antagonists mecamylamine, neosurugatoxin, and d-tubocurarine but not alpha-bungarotoxin [12].
• These techniques include nicotine chewing gum, skin patches, nasal sprays, and inhalers, as well as pharmacotherapies such as mecamylamine and clonidine, serotonergic treatments such as buspirone, and antidepressants such as buproprion [13].
• Infusions of CPP, (+)-MK-801, (+)-HA966, CNQX, mecamylamine, atropine, or 3-[[(3,4-dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid (CGP 52432) into the VTA did not modify extracellular dopamine in the nucleus accumbens [14].

Chemical compound and disease context of mecamylamine

• CONCLUSIONS: Agonist-antagonist therapy, consisting of the nicotine patch with oral mecamylamine, may substantially improve current smoking cessation treatment [8].
• In vitro studies with nicotine and preliminary positive experience with mecamylamine (Inversine), a nicotinic receptor antagonist, in the clinical treatment of Tourette's syndrome patients, further supports the receptor inactivation hypothesis [15].
• These were contrasted with the effects of alpha1-adrenoceptor antagonism (prazosin 0.5 mg/kg i.v. bolus, in the presence of cardiac block) or ganglion blockade (mecamylamine 4 mg/kg i.v. bolus) [16].
• The rapidly desensitising (within 100 ms) current in dorsal root ganglion cells was inhibited by methyllycaconitine, alpha-bungarotoxin and (+)-tubocurarine (concentrations giving half-maximal inhibition were approximately 40, 60 and 800 nm, respectively), but not by hexamethonium (100 microm) or mecamylamine (100 microm) [17].
• Nicotine-induced decreases in VTA electrical self-stimulation thresholds: blockade by haloperidol and mecamylamine but not scopolamine or ondansetron [18].

Biological context of mecamylamine

• With the same potency (-)-nicotine stimulates tumor cell proliferation, an effect also blocked by mecamylamine [19].
• Treatment of cells with mecamylamine, a noncompetitive antagonist, did not change receptor levels or alter (-)-nicotine-evoked up-regulation [20].
• In the presence of mecamylamine, therefore, nAChRs acquire the new property of operating as coincidence detectors for concomitant changes in membrane potential and receptor occupancy [21].
• Whereas the antagonists dihydro-beta-erythroidine (IC50 of 3-6 nM) and methyllycaconitine (IC50 of 40-135 nM) were not selective between high- and low-sensitivity alpha4beta2, chlorisondamine, mecamylamine, and d-tubocurarine were, respectively, 100-, 8-, and 5-fold selective for the alpha4beta2 subform with low sensitivity to acetylcholine [22].
• Mecamylamine (1-10 microM) blocked indirect muscle twitches with no discernible effect on the membrane potential, overshoot, or amplitude of the action potential [23].

Anatomical context of mecamylamine

• A direct interaction of the drug with the alpha-BGT recognition site was not required for the increase in receptor number to occur; mecamylamine did not affect binding of alpha-BGT to chromaffin cells in culture in competition binding experiments, although d-tubocurarine did compete with alpha-BGT for binding to its recognition site [24].
• These results suggested that, at the nicotinic receptors of the neuromuscular junction, mecamylamine acted as a noncompetitive blocker, binding primarily to the receptor's open channel conformation [23].
• Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area [25].
• However, the maximal inhibition of responses achieved by alpha-conotoxin-MII (112 nM) was 44.9 +/- 5.4% for synaptosomes and 25.0 +/- 4.1% for slices, compared with an inhibition by 10 microM mecamylamine of 77.9 +/- 3.7 and 88.0 +/- 2.1%, respectively [26].
• We have previously shown that fourth ventricular administration of Nic rapidly elevated plasma ACTH levels, that a nicotinic cholinergic antagonist, mecamylamine, instilled into the fourth ventricle inhibited the ACTH response to iv Nic, and that Nic stimulated norepinephrine secretion in the hypothalamic paraventricular nucleus [27].

Associations of mecamylamine with other chemical compounds

• As in Sprague-Dawley rats, in SHRLJ and WKYLJ rats the cardiovascular and behavioral responses to intrathecal nicotine were significantly inhibited by mecamylamine, dihydro-beta-erthyroidine, and methyllycaconitine [28].
• The rank order of potency of nicotinic antagonists in blocking the function of this alpha3/beta4 receptor was mecamylamine > d-tubocurarine > dihydro-beta-erythroidine > hexamethonium [29].
• The acetylcholine receptor of the neuromuscular junction recognizes mecamylamine as a noncompetitive antagonist [23].
• The vasodilation induced by a single cigarette was greatly inhibited by pretreatment with mecamylamine or glibenclamide and attenuated by propranolol or Nomega-nitro-L-arginine methyl ester; the initial vasoconstriction was inhibited by seratrodast, a thromboxane A2 receptor antagonist (n=6 in each case) [30].
• Twenty-three cocaine-dependent patients, all cigarette smokers, were randomly assigned to mecamylamine (2.5 mg tablet) or placebo in a single-dose, placebo-controlled, crossover, double-blind study [31].

Gene context of mecamylamine

• Mecamylamine (non-selective nicotinic receptor inhibitor), alpha-bungarotoxin (alpha7 nicotinic receptor inhibitor) could block Ca2+ accumulation, and then, prevented the phosphorylation on ERK1/2 and p38 [32].
• These (+/-)-epibatidine effects on FGF-2 expression were antagonized by the non-competitive nAChR antagonist mecamylamine, indicating an involvement of nicotinic receptors [33].
• Acetylcholine-induced AVP release is antagonized by atropine or mecamylamine, indicating that both muscarinic and nicotinic receptors are mediating the cholinergic effect in these brain regions [34].
• The P2X purinoceptor blocker, suramin (50 microM) or a nicotinic ACh receptor (nAChR) blocker (hexamethonium, 100 microM; mecamylamine, 1 microM) only partially inhibited these responses, but together, blocked almost all activity [35].
• In animals treated with mecamylamine the regional haemodynamic effects of the higher dose endothelin-1 were not different from those in animals with intact baroreflexes [36].

Analytical, diagnostic and therapeutic context of mecamylamine

• The nature of the increase in the number of toxin-binding sites in chromaffin cells observed after treatment with d-tubocurarine or mecamylamine was subsequently investigated [24].
• Only mecamylamine, however, produced a perfusion deficit in parietotemporal cortex [37].
• Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study [38].
• In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg) [39].
• Erysodine (0.32-32 mg/kg) and mecamylamine (0.32-3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule [40].

References