Design, synthesis, and structure-activity relationship of tropane muscarinic acetylcholine receptor antagonists.
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.
Lainé
Dramane I
DI
Respiratory CEDD, GlaxoSmithKline, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA. dramane.i.laine@gsk.com
Wan
Zehong
Z
Yan
Hongxing
H
Zhu
Chongjie
C
Xie
Haibo
H
Fu
Wei
W
Busch-Petersen
Jakob
J
Neipp
Christopher
C
Davis
Roderick
R
Widdowson
Katherine L
KL
Blaney
Frank E
FE
Foley
James
J
Bacon
Alicia M
AM
Webb
Edward F
EF
Luttmann
Mark A
MA
Burman
Miriam
M
Sarau
Henry M
HM
Salmon
Michael
M
Palovich
Michael R
MR
Belmonte
Kristen
K
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
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