Epibatidine nicotinic receptor agonist

A wide variety of synthetic processes have been rendered asymmetric through the use of a chiral catalyst. In addition to the types of reaction described above, chiral transition metal catalysts have been used to influence the stereochemical course of isomerization, cyclization, and coupling reactions. As an example, an approach towards the natural product (-)-epibatidine (158) was recently reported by Namyslo and Kaufmann (166). Epibatidine is a potent analgesic and a nicotinic receptor agonist. The synthesis involves an asymmetric Heck-type hydroarylation between the bicyclic alkene (155) and pyridyl iodide (156). A number of bidentate chiral li-... 

Epibatidine, an alkaloid discovered in 1974, has attracted considerable interest because it appears to be the first compound exhibiting analgesic activity as a selective and potent nicotinic receptor agonist. Campillo et al.207 performed a theoretical study on the conformational profile of epibatidine and its protonated form (Figure 24) using molecular mechanics, semi-empirical and ab... 

Analgesic profile of the nicotinic acetylcholine receptors agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain. Pain 2000, 86, 113-118. 

Sullivan, J. P., Bannon, A. W. Epibatidine Pharmacological properties of a novel nicotinic acetylcholine receptor agonist and analgesic agent, CNS Drug Rev. 1996, 2, 21-39. 

Kesingland AC, Gentry CT, Panesar MS, Bowes MA, Vernier J-M, Cube R, Walker K, Urban L (2000) Analgesic Profile of the Nicotinic Acetylcholine Receptor Agonists, (+)-Epibatidine and ABT-594 in Models of Persistent Inflammatory and Neuropathic Pain. Pain 86 113... 

Figure 7.3. Similar alkaloids to anatoxin-a with agonist activity for nicotinic receptors (A) (-)-epibatidine,...

A series of pyridyl ethers, typified by (81) and (82), exhibited high binding affinity at cytisine rat forebrain sites (cytisine is a nicotinic receptor partial agonist), but only moderate affinity at H-epibatidine sites (109, 130). 

The different combinations of recombinant neuronal nicotinic receptors differ in their sensitivity to agonists. The list of nicotinic agonists is long and consists of both natural compounds such as choline, nicotine, cytisine, lobeline, epibatidine, anabaseine, and synthetic compounds such as tetramethylammo-... 

In other instances such apparent hybrid activities could be missing or less prominent, as shows the example of epibatidine, a powerful alkaloid from the skin of several arrow poison frogs. Synthetic (+)- and natural (-)-epibatidine have potent agonist activity at ganglionic-type nicotinic receptors. The epibatidines have little or no activity at a variety of other central receptors, including opioid receptors, muscarinic receptors, adrenergic receptors, dopamine receptors, serotonin receptors, and GABA receptors [81]. 

Che D, Wegge T, Stubbs MT, Seitz G, Meier H, Methfessel C (2001) rt>-2-(Pyridazin-4-yl)-7-azabicyclo[2.2.1]heptanes syntheses and nicotinic acetylcholine receptor agonist activity of potent pyridazine analogues of (+/-)-epibatidine. J Med Chem 44 47-57... 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

Acetylcholine receptors - nicotinic agonists Natural alkaloids include anatoxin, epibatidine and nicotine. 

The a4p2 nAChR is the predominant heteromeric receptor in the brain, binds nicotine and other nicotinic agonists, e.g. cytisine and epibatidine. As a principal nicotinic AChR is more ubiquitous and is predominant in cortex, striatum, superior colliculus, lateral geniculate nucleus and cerebellum. When activated it facilitates excitatory inputs and is present very early in the developing brain in various brain regions. 

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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