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Synthesis, Characterization, and Metabolism Studies of Fluspidine Enantiomers
Author(s) -
Holl Katharina,
Falck Evamaria,
Köhler Jens,
Schepmann Dirk,
Humpf HansUlrich,
Brust Peter,
Wünsch Bernhard
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300322
Subject(s) - enantiomer , chemistry , radiosynthesis , metabolite , stereochemistry , ligand (biochemistry) , nucleophile , racemic mixture , receptor , organic chemistry , in vivo , biochemistry , catalysis , microbiology and biotechnology , biology
The enantiomers of the potent σ 1 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 [ 18 F]( R )‐ 1 and [ 18 F]( 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 σ 1 receptor affinity and selectivity against the σ 2 receptor. ( R )‐Fluspidine (( R )‐ 1 ) is the eutomer, with a K i value of 0.57 n M 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 .