From benzodioxane to 1,4-dioxane scaffold in the design of 5-HT1A serotoninergic full agonists from α1-adrenergic antagonists

The quite planar 1,4-benzodioxane structure of the non-subtype selective α1-adrenergic antagonist WB 4101 (1) [1] has successfully been replaced by the less conformationally constrained 1,4-dioxane nucleus substituted in its positions 5 or 6 with one or two pendant phenyl rings. Indeed, the compounds characterized by N-(6,6-diphenyl-1,4dioxan-2ylmethyl)-2-phenoxyethanamine structure, where R is 2,6-OCH3 (2), 2-OCH3 (3), or H (4), showed full 5-HT1A receptor agonism, selective α1D-adrenergic antagonism or significant cytotoxic activity, respectively [2]. Considering that a high degree of homology exits between 5-HT1A and α1-adrenergic receptors [3] and WB 4101 itself displays 5-HT1A affinity, the improved 5-HT1A/α1-adrenergic profile of compound 2 appeared noteworthy. Therefore, to identify stereochemical requirements for the selective recognition of the above mentioned biological targets, the derivatives 2-4 have been resolved into the corresponding enantiomers. In addition, novel ligands, bearing one or two phenyl groups in positions 2 or 3 of the 1,4-dioxane scaffold, have been prepared and studied. References [1]. Mottram, D. R.; Kapur, H. J. Pharm. Pharmacol., 27, 295-296, 1975. [2]. Quaglia, W.; Piergentili, A.; Del Bello, F.; Farande, Y.; Giannella, M.; Pigini, M.; Rafaiani, G.; Carrieri, A.; Amantini, C.; Lucciarini, R.; Santoni, G.; Poggesi, E.; Leonardi, A. J. Med. Chem., 51, 6359-6370, 2008. [3]. Trumpp-Kallmeyer, S.; Hoflack, J.; Bruinvels, A.; Hibert, M. J. Med. Chem., 35, 3448-3462, 1992.