Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?

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• 作者：Frauke Weber ; Stefanie Brune ; Frederik Börgel ; Carsten Lange ; Katharina Korpis ; Patrick J. Bednarski ; Erik Laurini ; Maurizio Fermeglia ; Sabrina Pricl ; Dirk Schepmann ; Bernhard Wünsch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5505-5519
• 全文大小：646K
• 年卷期：0
• ISSN：1520-4804

文摘

Stereoisomeric 2,5-diazabicyclo[2.2.2]octanes 14 and 15 were prepared in a chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping of the intermediate hemiketal anion with Me₃SiCl. The σ₁ affinity was tested using membrane preparations from animal (guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations based on a 3D homology model of the σ₁ receptor. The good correlation between K_i values observed in the σ₁ assays and calculated free binding energy, coupled with the identification of four crucial ligand/receptor interactions, allowed the formulation of structure–affinity relationships. In an in vitro antitumor assay with seven human tumor cell lines, the bicyclic compounds inhibited selectively the growth of the cell line A427, which is due to induction of apoptosis. In this assay, the compounds behave like the known σ₁ receptor antagonist haloperidol.