Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

Ida Nymann Petersen; François Crestey; Anders A Jensen; Dinesh C Indurthi; Henrik Pedersen; Jesper T Andreasen; Thomas Balle; Jesper L Kristensen

doi:10.1021/acsmedchemlett.5b00028

Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

ACS Med Chem Lett. 2015 Mar 4;6(4):472-5. doi: 10.1021/acsmedchemlett.5b00028. eCollection 2015 Apr 9.

Authors

Ida Nymann Petersen¹, François Crestey¹, Anders A Jensen¹, Dinesh C Indurthi², Henrik Pedersen³, Jesper T Andreasen¹, Thomas Balle², Jesper L Kristensen¹

Affiliations

¹ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
² Faculty of Pharmacy, University of Sydney , Sydney, NSW 2006, Australia.
³ Discovery Chemistry and DMPK , H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.

Abstract

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.

Keywords: Bridged-nicotine analogue; Negishi cross-coupling reaction; nAChRs; oocyte; selective antagonist.