Substituted benzylaminoalkylindoles with preference for the σ2 binding site

In the attempt to develop new σ ligands we synthesized a series of N-benzyl-3-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylpropan-1-amines and N-benzyl-4-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylbutan-1-amines variously substituted on the phenyl ring. The displacement percentages of [3H]-DTG and [3H]-(+)-pentazocine determined in rat liver homogenates by these compounds at the fixed 100 nM concentration have been determined as a preliminary evaluation of their σ1 and σ2 affinity, respectively.The results suggested that the phenyl substituents may positively modulate, in comparison with the unsubstituted compound, the ability to displace [3H]-DTG from σ2 sites, whereas the same phenyl substituents reduced the displacement percentages of [3H]-(+)-pentazocine from σ1 sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for σ2 over σ1 receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest σ2 affinity (σ2Ki = 5.9 nM) and an appreciable σ2 over σ1 selectivity (σ1Ki/σ2Ki = 22). The obtained results suggest that a butylene chain separating the indole moiety from variously substituted benzylamino groups may be required to their interaction with a hypothetical secondary σ2 binding site.

Graphical abstractA series of substituted N-benzyl-3-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylpropan-1-amines (n = 3) and N-benzyl-4-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylbutan-1-amines (n = 4) have been synthesized and a preliminary evaluation of their affinity towards σ1 and σ2 receptors was performed by radioligand binding assay.Figure optionsDownload full-size imageDownload as PowerPoint slideThe results suggested that the phenyl substituents positively affected the ability to displace [3H]-DTG from σ2 sites, whereas the same substituents reduced the ability to displace [3H]-(+)-pentazocine from σ1 sites. For the most active compounds competition concentration–response curves were generated. Compounds with n = 4 displayed the greatest σ2 over σ1 receptor affinity. The butylene derivative 2,4-dimethyl substituted on phenyl ring displayed the greatest σ2 affinity (σ2Ki = 5.9 nM) and an appreciable σ2 over σ1 selectivity (σ1Ki/σ2Ki = 22).