Nicotinic acetylcholine receptors antagonist

Turek, J.W., Kang, C.H., Campbell, J.E., Americ, S.P., Sullivan, J.P. A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain. J. Neurosci. Methods. 61 113, 1995. 

Schrimpf, M.R., Tietje, K.R., Toupence, R.B., Ji, J., Basha, A. (Abbott Laboratories) New N-substituted diazabicyclic compounds are nicotinic acetylcholine receptor antagonists, WO0181347 (2001). 

A similar strategy was utilized to construct indolizidinone 40 (Scheme 16), a designed mimic of the neurotoxic loop of erabutoxin b, a nicotinic acetylcholine receptor antagonist. 86 ... 

Pyrazole-based COX-inhibitors were synthesized using Pd/C as a heterogeneous and ready-filterable palladium source. Electron-deficient boronic acids coupled well while orf/zo-substitulcd and electron-rich boronic acid were less reactive (Scheme 62) [146]. The same team also developed a two-step and one-pot procedure for the synthesis of styrene-based nicotinic acetylcholine receptor antagonists. 

The nicotinic acetylcholine receptor antagonist ( )-epibatidine 285 is a potent, non-opioid analgesic that can be prepared by a cross-coupling reaction [100]. The advanced intermediate 284 was assembled by the Pd-catalyzed reaction of 282 with 283. o... 

Dutton, J.L., Graik, D.J. alpha-Conotoxins nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads. Curr. Med. Chem. 2001, 8, 327-344... 

Martinez, J.S. et al., Alpha-Conotoxin El, a new nicotinic acetylcholine receptor antagonist with novel selectivity, Biochemistry 34, 14519, 1995. 

Jimenez, E.C., Olivera, B,M., and Teichert, R.W. (2007) aC-Conotoxin PrXA A new family of nicotinic acetylcholine receptor antagonists. 

Curare is a generic term for various South American arrow poisons. Curare has been used for centuries by the Indians along the Amazon and Orinoco rivers for immobilizing and paralyzing wild animals used for food. Preparations of curare are derived from Strychnos species, which contain quaternary neuromuscular alkaloids like tubocurarine. Tubocurarine is a potent antagonist at the nicotinic acetylcholine receptor. 

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

Arias, H.R. Localization of agonist and competitive antagonist binding sites on nicotinic acetylcholine receptors. Neurochem. Int. 36 595, 2000. 

Mogg, A. J., Whiteaker, P, McIntosh, J.M., Marks, M., Collins, A.C., Wonnacott, S. Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. J. Pharmacol. Exp. Then 302 197, 2002. 

An even simpler protocol for performing nucleophilic substitutions (aminations) and Suzuki reactions in one pot was reported by the Organ group for the generation of a 42-member library of styrene-based nicotinic acetylcholine receptor (nAChR) antagonists (Scheme 6.21) [49]. After considerable experimentation, the authors found that simultaneous nucleophilic displacement and Suzuki coupling could be carried out very effectively by charging the microwave process vessel with the palladium catalyst (0.5 mol% palladium-on-charcoal), the boronic acid [R1B(OH)2], the... 

Xie Y, Cohen JB. 2001. Contributions of Torpedo nicotinic acetylcholine receptor yTrp-55 and 5Trp-57 to agonist and competitive antagonist function. J Biol Chem 276 (4) 2417. 

Sullivan D, Chiara DC, Cohen JB. 2002. Mapping the agonist binding site of the nicotinic acetylcholine receptor by cysteine scanning mutagenesis antagonist footprint and secondary structure predictions. Mol Pharmacol 61 ... 

Decker MW, Anderson DJ, Brioni ID, DonneUy-Roberts DL, Kang CH, O Neill AB, Piattoni-Kaplan M, Swanson S, SuUivan IP (1995) Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors, Eur J Pharmacol 280 79-89 Dekeyne A, Girardon S, MUlan Ml (1999) Discriminative stimulus properties of the novel serotonin (5-HT)2c receptor agonist, Ro 60-0175 a pharmacological analysis. Neuropharmacology 38 415-423... 

Mecamylamine is a noncompetitive antagonist at the nicotinic acetylcholine receptor site. If mecamylamine could effectively block the physiological and reinforcing effects of cigarette smoking, this should, in theory, lead to eventual extinction of the behavior. When mecamylamine is administered to smokers, it has increased rather than decreased ad libitum smoking behavior, presumably due to smokers... 

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

ANTAGONIZING ACETYLCHOLINE Curare, found in a resinous extract of the plants Chondrodendrott tomentosum and Strychnos toxifera from the Orinoco and Amazon basins in South America, is an antagonist at nicotinic acetylcholine receptors. Curare does not cross the blood—brain barrier, and therefore its actions are expressed only outside of the brain at the neuromuscular junction where neurons control muscles. Curare is extremely lethal for one simple reason—it blocks the nicotinic receptors located on the diaphragm therefore, death from curare results from asphyxiation. Imagine you ve been shot by a curare-tipped arrow you d be awake, fully aware of having been shot, yet completely unable to move, speak, or, ultimately, breathe. 

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