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Bhatti BS, Strachan JP, Breining SR, Miller CH, Tahiri P, Crooks PA, Deo N, Day CS, Caldwell WS: 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. J Org Chem. 2008 May 2;73(9):3497-507. Epub 2008 Mar 26.
In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 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 alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo [2.2.2] octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo [3.2.2] nonane series. |
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