title: Design, synthesis, and structure-activity relationship of tropane muscarinic acetylcholine receptor antagonists.
abstract: Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.
authors.affiliation: Respiratory CEDD, GlaxoSmithKline, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA. dramane.i.laine@gsk.com
authors.forename: Dramane I
authors.initials: DI
authors.lastname: Lainé
authors.forename: Zehong
authors.initials: Z
authors.lastname: Wan
authors.forename: Hongxing
authors.initials: H
authors.lastname: Yan
authors.forename: Chongjie
authors.initials: C
authors.lastname: Zhu
authors.forename: Haibo
authors.initials: H
authors.lastname: Xie
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Jakob
authors.initials: J
authors.lastname: Busch-Petersen
authors.forename: Christopher
authors.initials: C
authors.lastname: Neipp
authors.forename: Roderick
authors.initials: R
authors.lastname: Davis
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Widdowson
authors.forename: Frank E
authors.initials: FE
authors.lastname: Blaney
authors.forename: James
authors.initials: J
authors.lastname: Foley
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Bacon
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: Henry M
authors.initials: HM
authors.lastname: Sarau
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.forename: Michael R
authors.initials: MR
authors.lastname: Palovich
authors.forename: Kristen
authors.initials: K
authors.lastname: Belmonte
mesh_terms: D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000502:physiology; D043585:Receptor, Muscarinic M2 / Q000502:physiology; D043587:Receptor, Muscarinic M3 / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C543935:(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo( 3.2.1)octane bromide; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D014326:Tropanes; D002118:Calcium