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.