title: Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists.
abstract: A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.
authors.affiliation: GlaxoSmithKline, Respiratory CEDD, 709 Swedeland Road, P.O. Box 1539, King of Prussia, Pennsylvania 19406-0939, USA. dramane.i.laine@gsk.com
authors.forename: Dramane I
authors.initials: DI
authors.lastname: Lainé
authors.forename: Brent
authors.initials: B
authors.lastname: McCleland
authors.forename: Sonia
authors.initials: S
authors.lastname: Thomas
authors.forename: Christopher
authors.initials: C
authors.lastname: Neipp
authors.forename: Brian
authors.initials: B
authors.lastname: Underwood
authors.forename: Jeremy
authors.initials: J
authors.lastname: Dufour
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Widdowson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Palovich
authors.forename: Frank E
authors.initials: FE
authors.lastname: Blaney
authors.forename: James J
authors.initials: JJ
authors.lastname: Foley
authors.forename: Edward F
authors.initials: EF
authors.lastname: Webb
authors.forename: Mark A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: Miriam
authors.initials: M
authors.lastname: Burman
authors.forename: Kristen
authors.initials: K
authors.lastname: Belmonte
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon