In the attempt to develop new sigma 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 [H-3]-DTG and [H-3]-(+)-pentazocine determined in rat liver homogenates by these compounds at the fixed 100 nM concentration have been determined as a preliminary evaluation of their sigma(1) and sigma(2) affinity, respectively.The results suggested that the phenyl substituents may positively modulate, in comparison with the unsubstituted compound, the ability to displace [H-3]-DTG from sigma(2) sites, whereas the same phenyl substituents reduced the displacement percentages of [H-3]-(+)-pentazocine from sigma(1), sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for sigma(2) over sigma(1) receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest sigma(2) affinity (sigma K-2(i) = 5.9 nM) and an appreciable sigma(2) over sigma(1) selectivity (sigma K-1(i)/sigma K-2(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 sigma(2) binding site. (C) 2007 Elsevier Masson SAS. All rights reserved.
