Structure-affinity relationships of fluorinated spirocyclic σ2 receptor ligands with an exocyclic benzylamino moiety.

Structure-affinity relationships of fluorinated spirocyclic σ2 receptor ligands with an exocyclic benzylamino moiety.
ChemMedChem. 2019 Jun 12;:
Authors: Wünsch B, Bergkemper M, Kronenberg E, Schepmann D, Ludwig FA, Brust P
Abstract
In order to detect a potent and selective σ2 receptor ligand appropriate for the development as PET tracer several fluorinated analogs of the spirocyclic lead compounds trans-6 and cis-6 were designed. In multi-step syntheses, an F-atom was introduced directly or as 2-fluoroethoxy moiety at the 2-benzopyran scaffold, at the dimethylbenzylamino moiety or at the central amino moiety. In receptor binding studies with radioligands the σ1 and σ2 receptor affinity was determined. With respect to σ2 affinity and σ2: σ1 selectivity cis-configured 5-fluorobenzopyran cis-15c (Ki(σ2) = 51 nM) and fluoromethyl derivative cis-28e (Ki(σ2) = 57 nM) represent the most promising ligands. Combination of both structural elements in one molecule (cis-28c: Ki(σ2) = 874 nM) resulted in reduced σ2 and σ1 affinity. Methylation of secondary amines led to tertiary methylamines 29-31 with moderate affinity towards both σ receptor subtypes.
PMID: 31189022 [PubMed - as supplied by publisher]

Source: ChemMedChem - June 11, 2019 Category: Chemistry Authors: Wünsch B, Bergkemper M, Kronenberg E, Schepmann D, Ludwig FA, Brust P Tags: ChemMedChem Source Type: research