Structure-activity relationships in 1,4-benzodioxan-related compounds. 9.From 1,4-benzodioxan to 1,4-dioxane ring as a promising template of novel alpha(1D)-adrenoreceptor antagonists, 5-HT1A full agonists, and cytotoxic agents.

Novel 1,4-dioxane compounds structurally related to WB 4101 (1) were prepared in order to investigate the possibility that the quite planar 1,4-benzodioxane template of 1 might be replaced by the less conformationally constrained 1,4-dioxane ring. The biological profiles of the new compounds were assessed using binding assays at human cloned alpha1-adrenoreceptor (alpha1-AR) subtypes and 5-HT1A receptors, expressed in Chinese hamster ovary and HeLa cell membranes, respectively, and by functional experiments in isolated rat vas deferens (alpha1A), spleen (alpha1B), and aorta (alpha1D). Moreover, the cytotoxic effects of the novel compounds were determined in PC-3 prostate cancer cells. The results showed that the properly substituted 1,4-dioxane nucleus proved to be a suitable scaffold for selective alpha1D-AR antagonists (compound 14), potential anticancer agents (compound 13), and full 5-HT1A receptor agonists (compound 15). In particular, compound 15 may represent a novel lead in the development of highly potent 5-HT1A receptor full agonists useful as antidepressant and neuroprotective agents.