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
Targacept, Inc., 200 East 1st Street, Suite 300, Winston-Salem, North Carolina 27101-4165, USA.
J Org Chem. 2008 May 2;73(9):3497-507. doi: 10.1021/jo800028q. 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.
为了生成对α4β2和α7亚型受体具有选择性的烟碱型乙酰胆碱受体（nAChR）配体，我们设计并合成了一种天然存在的nAChR配体——新烟草碱的受限版本。2-(吡啶-3-基)-1-氮杂双环[2.2.2]辛烷、2-(吡啶-3-基)-1-氮杂双环[3.2.2]壬烷及其几种衍生物已通过相同的基本合成方法以对映选择性和外消旋方式合成。对于外消旋合成，N-(二苯基亚甲基)-1-(吡啶-3-基)甲胺与适当的溴代烷基四氢吡喃进行烷基化反应，得到中间体，这些中间体通过开环/氨基环化序列很容易转化为2-(吡啶-3-基)-1-氮杂双环[2.2.2]辛烷和2-(吡啶-3-基)-1-氮杂双环[3.2.2]壬烷。还通过N-(1-(吡啶-3-基亚乙基)丙-2-胺的烷基化反应实现了2-(吡啶-3-基)-1-氮杂双环[3.2.2]壬烷的另一种合成方法。对映选择性合成遵循相同的总体方案，但使用了由(+)-和(-)-2-羟基-3-蒎酮衍生的亚胺。手性高效液相色谱显示所需化合物的合成对映体过量（ee）>99.5%。随后使用X射线晶体学明确表征这些立体化学纯的nAChR配体。所有合成的化合物对α4β2 nAChR亚型均表现出高亲和力（Ki≤0.5 - 15 nM），一部分化合物对α7受体亚型具有高亲和力（Ki≤110 nM），在2-(吡啶-3-基)-1-氮杂双环[2.2.2]辛烷系列中观察到对α3β4（神经节）受体亚型具有选择性，在2-(吡啶-3-基)-1-氮杂双环[3.2.2]壬烷系列中对肌肉（α1βγδ）亚型具有选择性。
