Novel Potent 5-HT1a Agonists Selective over alpha1-Adrenoceptor Subtypes

The analogues 2-5 of the potent 5-HT1A receptor agonist and α1d-adrenoceptor (α1d-AR) antagonist 1 (1) were rationally designed and prepared to preliminarily evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety could exert any favorable effects on the affinity/activity at 5-HT1A receptor and selectivity over α1-AR subtypes. The methoxymethylenoxy derivative 6, an intermediate in the synthesis of 5, and the 2-pyridyl derivative 7 were also included in this study. The biological profiles of the novel compounds were assessed using radioligand competition binding assays. Moreover, lead 1 and the most interesting compounds 5 and 6 were also evaluated for their affinity for dopamine D2-like receptors. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported 1,4-dioxane ligands, a retrospective computational study, involving already published and the novel derivatives 2-7, and docking studies, using two 5-HT1A and one α1d receptor models generated by homology techniques, were performed.