Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors.
Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers, and determination of absolute configuration via enantioselective synthesis showed that the pharmacological activity resided almost exclusively in the (R)-enantiomer.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
Ida Nymann
IN
Petersen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
François
F
Crestey
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
Anders A
AA
Jensen
Faculty of Pharmacy, University of Sydney , Sydney, NSW 2006, Australia.
Dinesh C
DC
Indurthi
Discovery Chemistry and DMPK , H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
Henrik
H
Pedersen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
Jesper T
JT
Andreasen
Faculty of Pharmacy, University of Sydney , Sydney, NSW 2006, Australia.
Thomas
T
Balle
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
Jesper L
JL
Kristensen
Bridged-nicotine analogue; Negishi cross-coupling reaction; nAChRs; oocyte; selective antagonist