NAchR agonists

Although the antinociceptive potential of the natural product nicotine, an unselective nAChR agonist, was noticed as early as 1932 (Davis et al., 1932 Sahley and Berntson, 1979 Aceto et al., 1997 Rao et al., 1996 review Badio et al., 1995) interest in antinociceptive nicotinic agents was virtually non-existent for several decades. This changed dramatically in 1992 when another natural nACh receptor agonist was discovered and reported to be at least 200 times more potent than morphine (Spande et al., 1992 Holladay et al., 1997 Flores et al., 1999 Decker et al., 2001) ... 

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). 

V-Na+ CH blocker (169) (nAChR agonist) [antiarrhythmic, diuretic, insect feeding stimulant, hypoglycaemic, oxytocic, toxic]... 

Nicotine (1) is an old insecticide which acts on the postsynaptic nAChR. This botanic insecticide t pears to have interested a few chemists as a lead for a new insecticide. More than 30 years ago Yamamoto recognized the 3-pyridylmethyl amine residue as the essential part for the insecticidal activity by referring to the model of nAChR agonists by Beers and Reich [4], and prepared quite a number of 3-pyridylmethylamines [5,6]. Nicotine, being an acetylcholine mimic, can bind to the receptor by two elements (a) a... 

Isoxazole and Isothiazole Derivatives. Bioisosteric replacement of the pyridine ring in nicotine generated a series of novel isoxazole compounds that are selective and potent neuronal nAChR agonists, as exemplified by ABT-418 (71) (Table 14.8) (299). Among the variety of substituents examined at C3 cf the isoxazole, methyl turns out to be optimal, even though other substituents, such as C2-C4 linear alkyl, CF Br, and benzyl (not phenyl), still provide potent analogs. The 3-des-methyl... 

Because a crystal structure of nAChR is not available, the nAChR agonist binding site remains unknown. Nevertheless, the pharmacophore models and ir-cation studies should provide valuable guidance in the design of more selective and potent nAChR agonists for the treatment of CNS-related diseases. 

Pyrrilidine Ring-Opened Nicotin-oids. The nicotinoids, characterized as having an opened pyrrolidine ring, have been discussed in several reviews (273,293,295). Described herein is a series of trans-metanicotine analogs as nAChR agonists. 

Thus, the Ca flux assay, striatal slice assay and electrophysiology data considered together are consistent with the hypothesis that nAChR agonist-stimulated DA release is mediated through p2-containing nAChR sub-types, and that it is through this mechanism that (5)-6 stimulates DA release in vivo. 

Neuronal nAChR subtypes have an active role in neuronal growth, development and plasticity, " and neuronal signal modulation. When nicotine, a nonselective nAChR agonist, is administered, anxiolytic and cytoprotective effects are observed. " High doses of nicotine have been shown to be beneficial to individuals with cognitive and attention deficits, Parkinson s disease, Tourette s syndrome, and ulcerative colitis and... 

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