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

• Published in: Journal of medicinal chemistry Vol. 45; no. 18; pp. 4047 - 4054
• Main Authors: Ullrich, Thomas, Krich, Sylvia, Binder, Dieter, Mereiter, Kurt, Anderson, David J, Meyer, Michael D, Pyerin, Michael
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29-08-2002
• Subjects: Animals; Biological and medical sciences; Brain - metabolism; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Cholinergic system; Crystallography, X-Ray; In Vitro Techniques; Ligands; Medical sciences; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotine - analogs & derivatives; Nicotine - chemical synthesis; Nicotine - chemistry; Nicotine - pharmacology; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Receptors, Nicotinic - metabolism; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; Enantioselectivity; Rat; Angular nitrogen heterocycle; Nitrogen heterocycle; Ligand; Central nervous system; Cholinergic receptor; Structure activity relation; Chemical synthesis; Nicotinic receptor; Molecular rigidity; Rodentia; Tetracyclic compound; Tricyclic compound; X ray diffraction; In vitro; Spiran; Vertebrata; Biological fixation; Mammalia; Animal; Absolute configuration; Affinity; Brain (vertebrata); Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020916b

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 (K i = 4.79 nM) but also significant enantioselectivity over its antipode (K i = 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.