title: Discovery of novel α7 nicotinic acetylcholine receptor ligands via pharmacophoric and docking studies of benzylidene anabaseine analogs.
abstract: Based on pharmacophore elucidation and docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR, novel spirodiazepine and spiroimidazoline quinuclidine series have been designed. Binding studies revealed that some of hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype in comparison with most potent metabolite of GTS-21, 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine. Hydrophobicity and rigidity of the ligand also contribute into its binding affinity. We also describe alternative pharmacophoric features equidistant from the carbonyl oxygen atom of the conserved Trp-148 of the principal face, which may be exploited to further design diverse focused libraries targeting the α7 nAChR.
authors.affiliation: Targacept Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101 4165, USA. david.kombo@targacept.com
authors.forename: David C
authors.initials: DC
authors.lastname: Kombo
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Mazurov
authors.forename: Joseph
authors.initials: J
authors.lastname: Chewning
authors.forename: Philip S
authors.initials: PS
authors.lastname: Hammond
authors.forename: Kartik
authors.initials: K
authors.lastname: Tallapragada
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
authors.forename: Jason
authors.initials: J
authors.lastname: Speake
authors.forename: Daniel
authors.initials: D
authors.lastname: Yohannes
authors.forename: William S
authors.initials: WS
authors.lastname: Caldwell
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001597:Benzylidene Compounds; C579167:Chrna7 protein, human; D008024:Ligands; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C091713:anabaseine; D000691:Anabasine