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.
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/E163, A-1060 Vienna, Austria. thomas.ullrich@pharma.novartis.com
Thomas
T
Ullrich
Sylvia
S
Krich
Dieter
D
Binder
Kurt
K
Mereiter
David J
DJ
Anderson
Michael D
MD
Meyer
Michael
M
Pyerin
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