2. Academic Validation
  3. Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?

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

  • J Med Chem. 2016 Jun 9;59(11):5505-19. doi: 10.1021/acs.jmedchem.6b00585.
Frauke Weber 1,  Stefanie Brune 1,  Frederik Börgel 1,  Carsten Lange 2,  Katharina Korpis 2,  Patrick J Bednarski 2,  Erik Laurini 3,  Maurizio Fermeglia 3,  Sabrina Pricl 3 4,  Dirk Schepmann 1,  Bernhard Wünsch 1 5
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.
  • 2 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald , Friedrich-Ludwig-Jahn-Straße 17, 17487 Greifswald, Germany.
  • 3 Molecular Simulations Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste , Via Valerio 6, 34127 Trieste, Italy.
  • 4 National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste , Via Valerio 6, 32127 Trieste, Italy.
  • 5 Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, 48149 Münster, Germany.
PMID: 27156565 DOI: 10.1021/acs.jmedchem.6b00585
Abstract

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 Ki 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.

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