title: Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists.
abstract: A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.
authors.affiliation: Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA. jennifer.frost@abbott.com
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Frost
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Karin R
authors.initials: KR
authors.lastname: Tietje
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
authors.forename: Peter
authors.initials: P
authors.lastname: Curzon
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Jianquo
authors.initials: J
authors.lastname: Ji
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Kohlhaas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buckley
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Tino
authors.initials: T
authors.lastname: Dyhring
authors.forename: Philip K
authors.initials: PK
authors.lastname: Ahring
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009795:Octanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D009795:Octanes; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C082748:epibatidine; D002118:Calcium; C026728:octane