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.

[摘要]：(Heterocyclic Compounds (One Hetero Atom)) Section In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the a4b2 and a7 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 derivs. were prepd. 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-yl)ethylidene]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 compds. were synthesized in >99.5% ee. X-ray crystallog. was subsequently used to unambiguously characterize these stereochem. pure nAChR ligands. All compds. synthesized exhibited high affinity for the a4b2 nAChR subtype, a subset bound with high affinity for the a7 receptor subtype, selectivity over the a3b4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (a1bgd) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.

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