7-Azabicyclo[2.2.1]heptane as a scaffold for the development of selective sigma-2 (蟽₂) receptor ligands

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• 作者：Samuel D. Banister^a ; ^b ; Louis M. Rendina^a ; Michael Kassiou^a ; ^b ; ^c ; ^{michael.kassiou@sydney.edu.au}
• 关键词：Azanorbornanes ; Pyrrolidines ; Sigma receptors ; CNS ; Structure&ndash ; activity relationships
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 June, 2012
• 卷：22
• 期：12
• 页码：4059-4063
• 文件大小：396 K

摘要

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 蟽 ligands. In vitro competition binding assays against 蟽 receptors revealed that arylalkyl N-substituents conferred selectivity for the 蟽₂ subtype, while alicyclic or polycarbocyclic substituents imparted high affinity for both subtypes. The 蟽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.