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

• Published in: Neuropharmacology 2004-06, Vol.46 (7), p.1023-1038
• Main Authors: Papke, Roger L, Meyer, Edwin M, Lavieri, Sophie, Bollampally, Sirisha R, Papke, Thaddeus A S, Horenstein, Nicole A, Itoh, Yoshitsugu, Porter Papke, Julia K
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzylidene Compounds - chemistry; Benzylidene Compounds - metabolism; Benzylidene Compounds - pharmacology; Brain - drug effects; Brain - metabolism; Dose-Response Relationship, Drug; Female; Male; Mice; Nicotinic Agonists - chemistry; Nicotinic Agonists - metabolism; Nicotinic Agonists - pharmacology; Protein Binding - drug effects; Protein Binding - physiology; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Structure-Activity Relationship; Xenopus laevis
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2004.01.005

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.