Substituted benzylaminoalkylindoles with preference for the sigma2 binding site.

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Citation

Mamolo MG, Zampieri D, Zanette C, Florio C, Collina S, Urbano M, Azzolina O, Vio L

Substituted benzylaminoalkylindoles with preference for the sigma2 binding site.

Eur J Med Chem. 2008 Oct;43(10):2073-81. Epub 2007 Sep 26.

PubMed ID
18069094 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
PentazocineSigma non-opioid intracellular receptor 1ProteinHumans
Yes
Agonist
Details