Structure–Affinity Relationships of Fluorinated Spirocyclic σ₂ Receptor Ligands with an Exocyclic Benzylamino Moiety

Abstract

To identify a potent and selective σ2 receptor ligand appropriate for development as a positron emission tomography (PET) tracer, several fluorinated analogues of the spirocyclic lead compounds trans‐ and cis‐6 (N‐(2,4‐dimethylbenzyl)‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine) were designed. In multistep syntheses, a fluorine atom was introduced directly or as a 2‐fluoroethoxy moiety on the 2‐benzopyran scaffold, on the dimethylbenzylamino moiety, or on the central amino moiety. The σ1 and σ2 receptor affinity was determined in receptor binding studies with radioligands. With respect to σ2 affinity and σ2/σ1 selectivity, cis‐N‐(2,4‐dimethylbenzyl)‐5‐fluoro‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐15 c, Ki(σ2)=51 nm) and cis‐N‐[4‐(fluoromethyl)‐2‐methylbenzyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐28 e, Ki(σ2)=57 nm) are the most promising ligands. The combination of both structural elements in one molecule, cis‐N‐[4‐(fluoromethyl)‐2‐methylbenzyl]‐5‐fluoro‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐28 c: Ki(σ2)=874 nm), resulted in decreased σ2 and σ1 affinity. Methylation of secondary amines led to three tertiary methylamines with moderate affinity for both σ receptor subtypes.

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

“…Attributing to the frequent recurrence of spirocycles in biologically active molecules and natural products, the asymmetric preparation of spirocyclic compounds and their biological evaluation has been an important research area for organic chemists [1–10] . Being essential constituents of natural products, drugs, living organisms and other products of utility to mankind in all walks of life, azetidin‐2‐one (β‐lactam) heterocycles have been recognized as a significant contribution of science to humanity [11] .…”