%0 Journal Article
%A Ullrich, Thomas
%A Krich, Sylvia
%A Binder, Dieter
%A Mereiter, Kurt
%A Anderson, David J.
%A Meyer, Michael D.
%A Pyerin, Michael
%D 2002
%T Conformationally Constrained Nicotines: Polycyclic, Bridged, and
Spiro-Annulated Analogues as Novel Ligands for the Nicotinic Acetylcholine
Receptor
%U https://acs.figshare.com/articles/journal_contribution/Conformationally_Constrained_Nicotines_Polycyclic_Bridged_and_Spiro-Annulated_Analogues_as_Novel_Ligands_for_the_Nicotinic_Acetylcholine_Receptor/3681405
%R 10.1021/jm020916b.s001
%2 https://ndownloader.figshare.com/files/5771253
%K affinity
%K compound
%K nicotinic acetylcholine receptor
%K rat forebrain preparation
%K K i
%K nM
%K Nicotinic Acetylcholine Receptor
%X A set of novel nicotine-related, conformationally constrained compounds, including tetracyclic,
bridged (4), and tricyclic, spiro-annulated (5) structures, were synthesized in a straightforward
manner and optically resolved in a convenient fashion with (+)- and (−)-O,O‘-di-p-toluoyltartaric
acids. Absolute configurations were determined by X-ray crystallography. These compounds
were evaluated for their ability to displace [3H]cytisine in a rat forebrain preparation and
compared to (−)-nicotine. Three substances emerged with high affinity in the low nanomolar
range. Moreover, one of these compounds ((+)-5b) showed not only high binding affinity (Ki =
4.79 nM) but also significant enantioselectivity over its antipode (Ki = 148 nM), supporting
the hypothesis that conformational restraint can lead to high-affinity ligands, which are
stereochemically discriminated by the nicotinic acetylcholine receptor and may feature optimum
locations of the active sites of the pharmacophore.
%I ACS Publications