Synthesis of 2-(Pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(Pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a Class of Potent Nicotinic Acetylcholine Receptor–Ligands

In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the α4β2 and α7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2....

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Bibliographic Details
Published in:	Journal of organic chemistry Vol. 73; no. 9; pp. 3497 - 3507
Main Authors:	Bhatti, Balwinder S, Strachan, Jon-Paul, Breining, Scott R, Miller, Craig H, Tahiri, Persida, Crooks, Peter A, Deo, Niranjan, Day, Cynthia S, Caldwell, William S
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 02-05-2008
Subjects:	Animals Bridged Bicyclo Compounds - chemical synthesis Bridged Bicyclo Compounds - chemistry Bridged Bicyclo Compounds - metabolism Chemistry Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Ligands Molecular Structure Organic chemistry Preparations and properties Pyridines - chemical synthesis Pyridines - chemistry Pyridines - metabolism Quinuclidines - chemical synthesis Quinuclidines - chemistry Quinuclidines - metabolism Rats Receptors, Nicotinic - chemistry Receptors, Nicotinic - metabolism Stereoisomerism Enantioselectivity Nitrogen heterocycle Ligand HPLC chromatography Chiral compound Selectivity Oxygen heterocycle Alkylation Ring cleavage Pyridine derivatives Characterization Racemic Amine Chemical synthesis Nicotinic receptor Biological receptor Molecular rigidity Anabasine Pyran derivatives Imine X ray diffraction Cyclization Affinity Enantiomeric excess Acetylcholine
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Summary:	In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the α4β2 and α7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (−)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the α4β2 nAChR subtype (K i ≤ 0.5–15 nM), a subset bound with high affinity for the α7 receptor subtype (K i ≤ 110 nM), selectivity over the α3β4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (α1βγδ) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.
Bibliography:	istex:84AF105BF0D9F7F6FB884D55D7C0E7256370ED97 General information and experimental procedures for preparation of starting materials; 1H NMR and 13C NMR spectra for all new compounds; X-ray crystallographic data for 59–62. This material is available free of charge via the Internet at http://pubs.acs.org. ark:/67375/TPS-72FJ7LNV-8 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3263 1520-6904
DOI:	10.1021/jo800028q