Neural nicotinic acetylcholine receptor

Anabaseine (201) Tetrahydro-pyridinyl pyridine derivative (a nicotinic compound) 3-(2,4-Dimethoxy benzylidene)-anabaseine (DMXBA GTS-21) (202) Neurology (Alzheimer s disease) Enhances cognition it acts as a partial agonist at neural nicotinic acetylcholine receptors. It binds to both the o4p2 and a subtypes, but activates only the a to a significant extent Phase I/II CoMentis 927-933... 

Simple substituted pyridines such as isoniazid (7) showed antibacterial activity. The structurally related ethionamide (8) is an active antibiotic prodrug against tuberculosis in humans. Nicotine (1) and epibatidine (9) are naturally occurring agonists of neural nicotinic acetylcholine receptors... 

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Ronde P, Nichols RA (1998) High calcium permeability of serotonin 5-HT3 receptors on presynaptic nerve terminals from rat striatum. J Neurochem 70 1094-1103 Rosenstein RE, Chuluyan HE, Cardinali DP (1990) Presynaptic effects of gamma-aminobutyric acid on norepinephrine release and uptake in rat pineal gland. J Neural Transm 82 131—40 Rousseau SJ, Jones IW, Pullar IA, Wonnacott S (2005) Presynaptic [alpha]7 and non-[alpha]7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro. Neuropharmacology 49 59... 

Engidawork E, Gulesserian T, Balic N, Cairns N, Lubec G (2001) Changes in nicotinic acetylcholine receptor subunits expression in brain of patients with Down syndrome and Alzheimer s disease. J Neural Transm Suppl (61) 211-222... 

The nicotinic acetylcholine receptors of the neural excitatory cholinergic system are the targets for both nicotine and neonicotinoids in mammals and insects. 

Nicotinic acetylcholine receptors regulate the flow of Na" " and K" " through the channels in the neural postsynaptic membranes. Opening and closing of the channels by acetylcholine maintains the dynamic ratio of the intracellular to extracellular concentrations of Na" " and K+ which is needed for the initiation of the electric signal in the postsynaptic neuron. 

The alkaloid (—)-galanthamine, isolated from Caucasian snow-drop Galanthus woronowii) and other plant sources, is a competitive and reversible acetylcholinesterase inhibitor and an allosteric modulator of the neural nicotine receptors for acetylcholine. Galanthamine hydrobromide (commercially available as Razadyne) finds application in the treatment of symptoms of Alzheimer s disease [101]. Since the isolation of galanthamine (256) from natural sources is quite expensive, several total syntheses have been developed to date. The synthetic strategy to galanthamine (256) developed by Cho et al. [102] includes a domino Stille/Diels-Alder reaction as the key step (Scheme 14.39). 

In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block neuromuscular transmission. With higher doses, local anesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking antiarrhythmic drugs such as quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher concentrations of bupivacaine (0.75%) have been associated with cardiac arrhythmias independent of the muscle relaxant used. 

AH of the nerve agents under consideration are anticholinesterase compounds and induce accumulation of the neurotransmitter acetylcholine (ACh) at neural synapses and neuromuscular junctions by phosphorylating acetylcholinesterase (AChE). Depending on the route of exposure and amount absorbed, the PNS and/or CNS can be affected and muscarinic and/or nicotinic receptors may be stimulated. Interaction with other esterases may also occur, and direct effects to the nervous system have been observed. 

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