title: 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.affiliation: Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267 JHMHSC, Gainesville, FL 32610-0267, USA. rlpapke@ufl.edu
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Meyer
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavieri
authors.forename: Sirisha R
authors.initials: SR
authors.lastname: Bollampally
authors.forename: Thaddeus A S
authors.initials: TA
authors.lastname: Papke
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Horenstein
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Itoh
authors.forename: Julia K
authors.initials: JK
authors.lastname: Porter Papke
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001597:Benzylidene Compounds; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor