Synthesis and σ receptor affinity of spiro[[2]benzopyran-1, 1′-cyclohexanes] with an exocyclic amino moiety in the 3′-position. Issue 2 (9th December 2020)

• Record Type: Journal Article
• Authors: Kronenberg, Elisabeth; Weber, Frauke; Schepmann, Dirk; Wünsch, Bernhard
• Is Part Of: RSC medicinal chemistry. Volume 12:Issue 2(2021)
• Page Start: 237
• Page End: 244
• Publication Date: 2020-12-09
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d0md00307g
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : Novel spirocyclic σ 1 ligands with defined distances between the basic amino moiety and the phenyl rings were designed, synthesized and pharmacologically evaluated, in order to analyze the structural features crucial for high σ 1 affinity. Abstract : The main functions of σ 1 receptors include the modulation of release and reuptake of neurotransmitters, the regulation of ion channels and the influence on intracellular signaling through modulation of calcium levels. Due to these properties, σ 1 receptors are interesting drug targets for the treatment of various neurological disorders, pain and cancer. In order to modify the distance between the pharmacophoric elements (the benzene ring of 2-benzopyran and an amino moiety), a set of spiro[[2]benzopyran-1, 1′-cyclohexan]-3′-amines was synthesized. The key step of the synthesis was a Parham cyclization of 1-bromo-2-(2-bromoethyl)benzene (6 ) with the mono ketal 7 of cyclohexane-1, 3-dione, which led in a one-pot reaction to the spirocyclic framework 8 . Reductive amination of ketone 9 stereoselectively provided secondary amines cis -4, which were methylated to afford tertiary amines cis -5 . Whereas spirocyclic compounds cis -4a and cis -5a bearing a benzyl moiety at the exocyclic amino moiety showed rather low σ 1 affinity, the corresponding cyclohexylmethyl derivatives cis -4b and cis -5b exhibited low nanomolar σ 1 affinity. The secondary amine cis -4b displayed the highest σ 1 receptor affinity ( K i = 5.4 nM) in this series. Methylation of the secondary amine cis -4b led to a slightly decreased σ 1 receptor affinity of cis -5b ( K i = 15 nM).