Fluorinated 2-Arylcyclopropan-1-amines – A new class of sigma receptor ligands. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Schinor, Benjamin; Hruschka, Svenja; Daniliuc, Constantin G.; Schepmann, Dirk; Wünsch, Bernhard; Haufe, Günter
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: Arylcyclopropanamines -- Fluorine -- σ Receptor ligands -- Stereoselective synthesis -- Structure-affinity-relationship -- Tranylcypromine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115726
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: A series of 34 cis/trans isomeric fluorine-substituted arylcyclopropylamines substituted with electron-donating or electron-withdrawing substituents in meta - or para -position were investigated regarding their σ1 and σ2 receptor affinity. Highlights: 2-Aryl-2-fluorocyclopropan-1-amines are discovered as new σ receptor ligands. Cis/trans isomeric title compounds are prepared in a four step sequence from meta - or para -substituted α-fluorostyrenes. Generally, para -substituted compounds showed higher σ1 and σ2 receptor affinity than the corresponding meta isomers. The trans -configured p -methoxy derivative was the most active σ1 receptor ligand ( K i = 4.8 nM), while the cis -configured p -trifluoromethyl derivative was the most active σ2 receptor ligand ( K i = 95 nM). Abstract: Stereoisomeric 2-aryl-2-fluoro-cyclopropan-1-amines have been discovered as a new class of σ receptor ligands showing different selectivity for the two subtypes of the receptor. Generally, compounds substituted in 4-position are much more active than corresponding 3-substituted isomers. trans -2-Fluoro-2-(4-methoxyphenyl)cyclopropan-1-amine (19a ) was the most potent ( K i = 4.8 nM) σ1 receptor ligand, while cis -2-fluoro-2-(4-trifluoromethylphenyl)cyclopropan-1-amine (20b ) was the most potent ( K i = 95 nM) σ2 receptor ligand.