463303-95-9Relevant academic research and scientific papers
Conformationally constrained nicotines: Polycyclic, bridged, and spiro-annulated analogues as novel ligands for the nicotinic acetylcholine receptor
Ullrich, Thomas,Krich, Sylvia,Binder, Dieter,Mereiter, Kurt,Anderson, David J.,Meyer, Michael D.,Pyerin, Michael
, p. 4047 - 4054 (2007/10/03)
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.
