Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity

Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl-N′-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ1 receptors. The imidazolidines possessed nanomolar σ1 affinities (Ki=6.45–53.5nM), and relatively low levels of subtype selectivity (σ2/σ1=58–237). However, the piperazines and diazepanes achieved picomolar σ1 interactions, with Ki ranges of 0.05–10.28 and 0.10–0.194nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ2 receptor, with σ1 selectivities of 143–16140 and 220–11542, respectively.