Substituted benzylaminoalkylindoles with preference for the σ 2 binding site

Abstract

In the attempt to develop new σ ligands we synthesized a series of N-benzyl-3-[1-(4-fluorophenyl)-1 H-indol-3-yl]- N-methylpropan-1-amines and N-benzyl-4-[1-(4-fluorophenyl)-1 H-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 σ 1 and σ 2 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 σ 2 sites, whereas the same phenyl substituents reduced the displacement percentages of [ 3H]-(+)-pentazocine from σ 1 sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for σ 2 over σ 1 receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest σ 2 affinity (σ 2 K i = 5.9 nM) and an appreciable σ 2 over σ 1 selectivity (σ 1 K i/σ 2 K i = 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 σ 2 binding site.