title: Synthesis, characterization, and metabolism studies of fluspidine enantiomers.
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 [(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 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster (Germany).
authors.forename: Katharina
authors.initials: K
authors.lastname: Holl
authors.forename: Evamaria
authors.initials: E
authors.lastname: Falck
authors.forename: Jens
authors.initials: J
authors.lastname: Köhler
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Humpf
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C558383:1'-benzyl-3-(2-fluoroethyl)-3H-spiro((2)benzofuran-1,4'-piperidine); C573194:4-methylbenzenesulfonic acid; D001557:Benzenesulfonates; D001572:Benzofurans; D005462:Fluorine Radioisotopes; D010880:Piperidines; D017480:Receptors, sigma
keywords: chiral resolution; fluorinated ligands; metabolism; sigma-1 receptors; spirocyclic piperidines