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Structure–Affinity Relationships of Fluorinated Spirocyclic σ 2 Receptor Ligands with an Exocyclic Benzylamino Moiety
Author(s) -
Bergkemper Melanie,
Kronenberg Elisabeth,
Schepmann Dirk,
Ludwig FriedrichAlexander,
Brust Peter,
Wünsch Bernhard
Publication year - 2019
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.201900284
Subject(s) - moiety , chemistry , amine gas treating , stereochemistry , benzopyran , piperidine , ligand (biochemistry) , tertiary amine , receptor , organic chemistry , biochemistry
Abstract To identify a potent and selective σ 2 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 σ 1 and σ 2 receptor affinity was determined in receptor binding studies with radioligands. With respect to σ 2 affinity and σ 2 /σ 1 selectivity, cis ‐ N ‐(2,4‐dimethylbenzyl)‐5‐fluoro‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine ( cis ‐ 15 c , K i (σ 2 )=51 n m ) and cis ‐ N ‐[4‐(fluoromethyl)‐2‐methylbenzyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine ( cis ‐ 28 e , K i (σ 2 )=57 n m ) 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 : K i (σ 2 )=874 n m ), resulted in decreased σ 2 and σ 1 affinity. Methylation of secondary amines led to three tertiary methylamines with moderate affinity for both σ receptor subtypes.