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

Abstract

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.

• Authors: Roger L Papke, Edwin M Meyer, Sophie Lavieri, Sirisha R Bollampally, Thaddeus A S Papke, Nicole A Horenstein, Yoshitsugu Itoh, Julia K Porter Papke
• Journal: Neuropharmacology (Neuropharmacology) Vol. 46 Issue 7 Pg. 1023-38 (Jun 2004) ISSN: 0028-3908 [Print] England
• PMID: 15081799 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzylidene Compounds
• Chrna7 protein, mouse
• Chrna7 protein, rat
• Nicotinic Agonists
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor

Topics

• Animals
• Benzylidene Compounds (chemistry, metabolism, pharmacology)
• Brain (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Female
• Male
• Mice
• Nicotinic Agonists (chemistry, metabolism, pharmacology)
• Protein Binding (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Nicotinic (metabolism)
• Structure-Activity Relationship
• Xenopus laevis
• alpha7 Nicotinic Acetylcholine Receptor