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Conformationally Constrained Nicotines:  Polycyclic, Bridged, and Spiro-Annulated Analogues as Novel Ligands for the Nicotinic Acetylcholine Receptor

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journal contribution
posted on 07.08.2002 by Thomas Ullrich, Sylvia Krich, Dieter Binder, Kurt Mereiter, David J. Anderson, Michael D. Meyer, Michael Pyerin
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.