Synthesis and receptor binding studies of novel 4,4-disubstituted arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as a new class of σ1 ligands

This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to σ1 and σ2 receptors, respectively. The σ1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to σ1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold σ1/σ2 selectivity ratio (Kiσ1 = 0.96 ± 0.05 nM and Kiσ2 = 91.8 ± 8.1 nM). A novel class of sigma-1 receptor ligands was formed by replacement of methylene group of N-arylalkyl-4-benzylpiperazine or piperidine derivatives with sulfonyl group. [Display omitted] •We developed a novel class of σ1 receptor ligands.•A sulfonyl group was replaced by a methylene group of previously reported scaffolds.•Identification of 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine as a σ ligand seems promising.•The σ1 receptor affinities of synthesized compounds increases in the order n = 1 > 0 > 2.