10.1021/jm020916b.s001 Thomas Ullrich Thomas Ullrich Sylvia Krich Sylvia Krich Dieter Binder Dieter Binder Kurt Mereiter Kurt Mereiter David J. Anderson David J. Anderson Michael D. Meyer Michael D. Meyer Michael Pyerin Michael Pyerin Conformationally Constrained Nicotines:  Polycyclic, Bridged, and Spiro-Annulated Analogues as Novel Ligands for the Nicotinic Acetylcholine Receptor American Chemical Society 2002 affinity compound nicotinic acetylcholine receptor rat forebrain preparation K i nM Nicotinic Acetylcholine Receptor 2002-08-07 00:00:00 Journal contribution 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 A set of novel nicotine-related, conformationally constrained compounds, including tetracyclic, bridged (<b>4</b>), and tricyclic, spiro-annulated (<b>5</b>) structures, were synthesized in a straightforward manner and optically resolved in a convenient fashion with (+)- and (−)-<i>O</i>,<i>O</i>‘-di-<i>p</i>-toluoyltartaric acids. Absolute configurations were determined by X-ray crystallography. These compounds were evaluated for their ability to displace [<sup>3</sup>H]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 ((+)-<b>5b</b>) showed not only high binding affinity (<i>K</i><sub>i</sub> = 4.79 nM) but also significant enantioselectivity over its antipode (<i>K</i><sub>i</sub> = 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.