Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?
| العنوان: | Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity? |
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| المؤلفون: | Carsten Lange, Frauke Weber, Patrick J. Bednarski, Maurizio Fermeglia, Bernhard Wünsch, Dirk Schepmann, Frederik Börgel, Stefanie Brune, Erik Laurini, Sabrina Pricl, Katharina Korpis |
| المصدر: | Journal of Medicinal Chemistry. 59:5505-5519 |
| بيانات النشر: | American Chemical Society (ACS), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Models, Molecular, 0301 basic medicine, Stereochemistry, Guinea Pigs, Antineoplastic Agents, Apoptosis, Ligands, Heterocyclic Compounds, 2-Ring, Piperazines, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Receptors, sigma, Structure–activity relationship, Receptor, Cell Proliferation, Sigma-1 receptor, Dose-Response Relationship, Drug, Molecular Structure, Bicyclic molecule, Cell growth, Chemistry, Ligand, Biological activity, 030104 developmental biology, Mechanism of action, 030220 oncology & carcinogenesis, Thermodynamics, Molecular Medicine, Drug Screening Assays, Antitumor, medicine.symptom |
| الوصف: | 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. |
| تدمد: | 1520-4804 0022-2623 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dcf03d726ba597ffbd869cae9faec2cbTest https://doi.org/10.1021/acs.jmedchem.6b00585Test |
| رقم الانضمام: | edsair.doi.dedup.....dcf03d726ba597ffbd869cae9faec2cb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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