477352-08-2Relevant academic research and scientific papers
Novel σ receptor ligands. Part 2. SAR of spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] with carbon substituents in position 3
Maier, Christoph A.,Wünsch, Bernhard
, p. 4923 - 4930 (2007/10/03)
Several spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] were synthesized and evaluated for their binding properties for σ1 and σ2 receptors. The key step for the introduction of a one carbon residue is the reaction of the cyclic methyl acetals 2a and 3a with trimethylsilyl cyanide to yield the nitriles 5 and 20. The reaction of the lactols 2b and 3b with stabilized phosphoranes affords spiropiperidines with a two carbon residue in position 3. In agreement with previously reported σ1 and σ2 receptor binding data, the investigated spiro compounds display higher affinity for σ1 vs σ2 receptors. Compounds with a cyano group in position 3 of the spirocycle show high σ1 receptor affinity and selectivity. The spirobenzopyran nitrile 5 and the homologous spirobenzofuran nitriles 20 and 23 show almost identical σ1 affinities, whereas the spirobenzopyran nitrile 13 with a methylene spacer is 10-fold less potent. Among the reported compounds, 1′-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4′-piperidinel -3-carbonitrile 5 represents the most potent σ1 receptor ligand with a Ki value of 1.54 nM and a σ1/σ2 selectivity ratio of 1030.
