title: Structure-activity studies of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes: a novel class of highly potent nicotinic receptor ligands.
abstract: The potential for nicotinic ligands with affinity for the α4β2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4β2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes.
authors.affiliation: Targacept, Inc. 200 East First Street, Suite 300, Winston-Salem, North Carolina 27101, USA. srbreining@gmail.com
authors.forename: Scott R
authors.initials: SR
authors.lastname: Breining
authors.forename: Matt
authors.initials: M
authors.lastname: Melvin
authors.forename: Balwinder S
authors.initials: BS
authors.lastname: Bhatti
authors.forename: Gary D
authors.initials: GD
authors.lastname: Byrd
authors.forename: Melanie N
authors.initials: MN
authors.lastname: Kiser
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Hepler
authors.forename: Dawn N
authors.initials: DN
authors.lastname: Hooker
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Reynolds
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Benson
authors.forename: Nikolai B
authors.initials: NB
authors.lastname: Fedorov
authors.forename: Serguei S
authors.initials: SS
authors.lastname: Sidach
authors.forename: J Pike
authors.initials: JP
authors.lastname: Mitchener
authors.forename: Linda M
authors.initials: LM
authors.lastname: Lucero
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.forename: Daniel
authors.initials: D
authors.lastname: Yohannes
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004594:Electrophysiology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008024:Ligands; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy*; D009538:Nicotine / Q000494:pharmacology*; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D009538:Nicotine; D002118:Calcium