Conformationally constrained nicotines: polycyclic, bridged, and spiro-annulated analogues as novel ligands for the nicotinic acetylcholine receptor.
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 [(3)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 ((+)-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.
Ullrich
Thomas
T
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/E163, A-1060 Vienna, Austria. thomas.ullrich@pharma.novartis.com
Krich
Sylvia
S
Binder
Dieter
D
Mereiter
Kurt
K
Anderson
David J
DJ
Meyer
Michael D
MD
Pyerin
Michael
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008024:Ligands; D008968:Molecular Conformation; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C465467:1,2,3,4,10,11-hexahydro-1-methylspiro(7H-2pyrindine-7,2'-2H-pyrrole); D001952:Bridged-Ring Compounds; D008024:Ligands; D011758:Pyrroles; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D009538:Nicotine