Synthesis,Characterization, and Metabolism Studies of Fluspidine Enantiomers |
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Authors: | Dr Katharina Holl Dr Evamaria Falck Dr Jens Köhler Dr Dirk Schepmann Prof Dr Hans‐Ulrich Humpf Prof Dr Peter Brust Prof Dr Bernhard Wünsch |
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Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie, Westf?lische Wilhelms‐Universit?t Münster, Corrensstr. 48, 48149 Münster (Germany);2. Institut für Lebensmittelchemie, Westf?lische Wilhelms‐Universit?t Münster, Corrensstr. 45, 48149 Münster (Germany);3. Helmholtz‐Zentrum Dresden‐Rossendorf, Institut für Radiopharmazeutische Krebsforschung Forschungsstelle Leipzig, Abteilung Neuroradiopharmaka, Permoserstr. 15, 04318 Leipzig (Germany) |
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Abstract: | The enantiomers of the potent σ1 ligand fluspidine ( 1 ) were prepared by using chiral preparative HPLC. Synthesis of racemic tosylate 2 and subsequent separation of enantiomers yielded (R)‐ 2 and (S)‐ 2 in excellent enantiomeric purities. The fluspidine enantiomers (R)‐ 1 and (S)‐ 1 were synthesized from (R)‐ 2 and (S)‐ 2 by nucleophilic substitution with tetra‐n‐butylammonium fluoride, affording (R)‐ 1 with 99.6 % ee and (S)‐ 1 with 96.4 % ee. Tosylates (R)‐ 2 and (S)‐ 2 can also serve as precursors for the radiosynthesis of enantiomerically pure radiotracers 18F](R)‐ 1 and 18F](S)‐ 1 . The absolute configuration of the pure enantiomers was elucidated by comparison of their CD spectra with a calculated CD spectrum of a simplified model compound. In receptor binding studies, both enantiomers displayed very high σ1 receptor affinity and selectivity against the σ2 receptor. (R)‐Fluspidine ((R)‐ 1 ) is the eutomer, with a Ki value of 0.57 nM and a eudysmic ratio of 4. Incubation of (R)‐ 1 and (S)‐ 1 with rat liver microsomes led to the identification of seven and eight metabolites, respectively. Although the S‐configured enantiomer formed additional metabolite (S)‐ 1‐3 , it is metabolically more stable than (R)‐ 1 . |
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Keywords: | chiral resolution fluorinated ligands metabolism spirocyclic piperidines sigma‐1 receptors |
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