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.

A 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 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).