title: SAR of α7 nicotinic receptor agonists derived from tilorone: exploration of a novel nicotinic pharmacophore.
abstract: The well-known interferon-inducer tilorone was found to possess potent affinity for the agonist site of the α7 neuronal nicotinic receptor (K(i)=56 nM). SAR investigations determined that both basic sidechains are essential for potent activity, however active monosubstituted derivatives can also be prepared if the flexible sidechains are replaced with conformationally rigidified cyclic amines. Analogs in which the fluorenone core is replaced with either dibenzothiophene-5,5-dioxide or xanthenone also retain potent activity.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6117, USA. michael.schrimpf@abbott.com
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schrimpf
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Sippy
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Frost
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
mesh_terms: D000818:Animals; D005449:Fluorenes / Q000737:chemistry*; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013994:Tilorone / Q000737:chemistry* / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D005449:Fluorenes; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D013994:Tilorone