Effects at a distance in α7 nAChR selective agonists: Benzylidene substitutions that regulate potency and efficacy

The potency and efficacy of α7 agonists page 2 Summary 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 α3β4 and α4β2 receptors, benzylidene anabaseine (BA) derivatives have high selectivity for the α7 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 α7 selectivity. In this study, we specifically investigated the influence of the benzylidene attachment to anabaseine on α7 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 α7 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 α7 and neuronal α3β4 and α4β2 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. analysis Abbreviations: BA the class of benzylidene anabaseine compounds 3-BA 3-benzylidene anabaseine GTS-21 3-(2,4-dimethoxybenzylidene)anabaseine 4OH-GTS-21 3-(2-methoxy,4-hydroxybenzylidene)anabaseine 4OH-BA 3-(4-hydroxybenzylidene)anabaseine 4-MeS-BA 3-(4-methylthiobenzylidene)anabaseine 4-CF 3-BA 3-(4-trifluoromethylbenzylidene)anabaseine Papke et al.