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 sigma 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 sigma(1) receptors. The imidazolidines possessed nanomolar sigma(1) affinities (K-i = 6.45-53.5 nM), and relatively low levels of subtype selectivity (sigma(2)/sigma(1) = 58-237). However, the piperazines and diazepanes achieved picomolar sigma(1) interactions, with K-i ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the sigma(2) receptor, with sigma(1) selectivities of 143-16140 and 220-11542, respectively. (c) 2012 Elsevier Ltd. All rights reserved.