Substituted benzylaminoalkylindoles with preference for the σ2 binding site

In the attempt to develop new s 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]-(þ)-pentazocine determined in rat liver omogenates by these compounds at the fixed 100 nM concentration have been determined as a preliminary evaluation of their s1 and s2 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 s2 sites, whereas the same phenyl substituents reduced the displacement percentages of [3H]-(þ)-pentazocine from s1 sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for s2 over s1 receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest s2 affinity (s2Ki ¼ 5.9 nM) and an appreciable s2 over s1 selectivity (s1Ki/s2Ki ¼ 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 s2 binding site.