The replacement of the 2-methoxy substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine improves the selectivity for 5-HT_1Areceptor over α₁-adrenoceptor and D₂-like receptor subtypes

N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT_1Areceptor and α_1d-adrenoceptor (α_1d-AR) ligand. Analogues 5–10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT_1Areceptor and improve selectivity over α₁-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT_1Aand α_1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT_1Areceptor with respect to α₁-ARs and D₂-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT_1Aselectivity profile and the highest potency at 5-HT_1Areceptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT_1Areceptor is involved.