title: Substituted benzylaminoalkylindoles with preference for the sigma2 binding site.
abstract: 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 [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 sigma1 and sigma2 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 sigma2 sites, whereas the same phenyl substituents reduced the displacement percentages of [3H]-(+)-pentazocine from sigma1 sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for sigma2 over sigma1 receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest sigma2 affinity (sigma2Ki=5.9 nM) and an appreciable sigma2 over sigma1 selectivity (sigma1Ki/sigma2Ki=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 sigma2 binding site.
authors: Department of Pharmaceutical Sciences, University of Trieste, P.ale Europa 1, 34127 Trieste, Italy. mamolo@units.it
authors: Maria Grazia
authors: MG
authors: Mamolo
authors: Daniele
authors: D
authors: Zampieri
authors: Caterina
authors: C
authors: Zanette
authors: Chiara
authors: C
authors: Florio
authors: Simona
authors: S
authors: Collina
authors: Mariangela
authors: M
authors: Urbano
authors: Ornella
authors: O
authors: Azzolina
authors: Luciano
authors: L
authors: Vio
mesh_terms: D000818:Animals; D001554:Benzene / Q000737:chemistry*; D001665:Binding Sites; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D007211:Indoles; D017480:Receptors, sigma; C106107:sigma-2 receptor; D001554:Benzene