Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Papke, R.L. et al.

Papke, Meyer, Lavieri, Bollampally, Papke, Horenstein, Itoh, Porter Papke,

Effects at a distance in alpha 7 nAChR selective agonists: benzylidene substitutions that regulate potency and efficacy.

Anabaseine is a marine worm toxin that is a relatively non-selective nicotinic agonist, activating both muscle-type and neuronal nicotinic acetylcholine receptors (nAChR) with varying efficacy. While anabaseine has significant activity with muscle-type and neuronal alpha 3 beta 4 and alpha 4 beta 2 receptors, benzylidene anabaseine (BA) derivatives have high selectivity for the alpha 7 receptor subtype. Two BA compounds with substituents at the 2 and 4 positions of the benzylidene ring, GTS-21 and 4OH-GTS-21, may have therapeutic potential for treating neuropathological disorders such as Alzheimer's disease due to their alpha 7 selectivity. In this study, we specifically investigated the influence of the benzylidene attachment to anabaseine on alpha 7 nicotinic receptor selectivity, as well as the effects of specific substituents at the 4- position of the benzylidene moiety. We demonstrate that benzylidene-attachment alone is sufficient to confer alpha 7 selectivity to anabaseine. Increased potency and receptor binding affinity was obtained with a 4-hydroxyl substitution. Two other 4-substituted benzylidene anabaseines, 3-(4'-methylthiobenzylidene)anabaseine (4-MeS-BA) and 3-(4-trifluoromethylbenzylidene) anabaseine (4-CF(3)-BA), offered very little agonist activity for any nicotinic receptors and instead were antagonists for both alpha 7 and neuronal alpha 3 beta 4 and alpha 4 beta 2 receptors. Since the relative amounts of agonist and antagonist activities for specific BA compounds vary with the specific drug/receptor combinations, benzylidene anabaseines provide valuable tools for nAChR drug-receptor structure-function relationships.[1]

References

Effects at a distance in alpha 7 nAChR selective agonists: benzylidene substitutions that regulate potency and efficacy. Papke, R.L., Meyer, E.M., Lavieri, S., Bollampally, S.R., Papke, T.A., Horenstein, N.A., Itoh, Y., Porter Papke, J.K. Neuropharmacology (2004) [Pubmed]

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