%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