School of Chemistry, The University of Sydney, NSW 2006, Australia.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):4059-63. doi: 10.1016/j.bmcl.2012.04.077. Epub 2012 Apr 30.
A series of N-substituted 7-azabicyclo[2.2.1]heptanes (12-17 and 22-25) and similarly substituted pyrrolidines (32-36 and 41-44) were synthesized as sterically-reduced, achiral analogs of adamantane- and trishomocubane-derived σ ligands. In vitro competition binding assays against σ receptors revealed that arylalkyl N-substituents conferred selectivity for the σ(2) subtype, while alicyclic or polycarbocyclic substituents imparted high affinity for both subtypes. The σ(2) binding and subtype selectivities of N-arylalkyl-7-azanorbornanes was generally greater than the analogously-substituted pyrrolidines, indicating that steric bulk and conformational restriction around the nitrogen atom are likely important for subtype discrimination.
一系列 N-取代的 7-氮杂双环[2.2.1]庚烷（12-17 和 22-25）和类似取代的吡咯烷（32-36 和 41-44）被合成作为金刚烷和三环癸烷衍生的 σ 配体的空间位阻减小的非手性类似物。与 σ 受体的体外竞争结合测定表明，芳基烷基 N-取代基赋予 σ(2)亚型选择性，而脂环族或多环碳环取代基赋予两种亚型高亲和力。N-芳基烷基-7-氮杂降冰片烷的 σ(2)结合和亚型选择性通常大于类似取代的吡咯烷，表明氮原子周围的空间位阻和构象限制对于亚型鉴别可能很重要。
