Synthesis and pharmacological evaluation of indole-based sigma receptor ligands

A series of novel indole-based analogs were prepared and their affinities for sigma receptors were determined using in vitro radioligand binding assays. The results of this study identified several compounds with nanomolar sigma-2 affinity and significant selectivity over sigma-1 receptors. In particular, 2-(4-(3-(4-fluorophenyl)indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9f) was found to display high affinity at sigma-2 receptors with good selectivity (σ-1/σ-2 = 395). The pharmacological binding profile for this compound was established with other relevant non-sigma sites.

Graphical abstractA series of novel indole-based analogs were prepared and their affinities for sigma receptors were determined.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Preparation and evaluation of a series of indoles as sigma receptor ligands. ► Identification of several sigma-2 selective derivatives. ► Extensive pharmacological profile characterization for the best compound.