Conformationally Constrained Nicotines: Polycyclic, Bridged, and
Spiro-Annulated Analogues as Novel Ligands for the Nicotinic Acetylcholine
Receptor
Thomas Ullrich
Sylvia Krich
Dieter Binder
Kurt Mereiter
David J. Anderson
Michael D. Meyer
Michael Pyerin
10.1021/jm020916b.s001
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.
2002-08-07 00:00:00
affinity
compound
nicotinic acetylcholine receptor
rat forebrain preparation
K i
nM
Nicotinic Acetylcholine Receptor