Conformationally Constrained Nicotines: Polycyclic, Bridged, and Spiro-Annulated Analogues as Novel Ligands for the Nicotinic Acetylcholine Receptor
2002-08-07T00:00:00Z (GMT) by
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.