Heteroaryloxy analogues of WB4101: synthesis and biological evaluation at alpha1-adrenoreceptor subtypes

The physiological role of the three α1-adrenoreceptor (α1-AR) subtypes (α1A, α1B and α1D) has been intensively investigated in recent years as well as their involvement in pathological disorders, in particular in hypertension and in lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Our research group has long been involved in designing new α1-AR ligands structurally related to 2-(2,6-dimethoxyphenoxy)ethylaminomethyl- 1 ,4-benzodioxane (WB4101), a potent α1 antagonist with a slight selectivity for α1A- and, to a minor extent, for α1D-ARs with respect to α1B-AR and 5-HT1A serotoninergic receptor. More recently, we have extensively investigated the role of the phenoxy moiety of WB4101 in the interaction with α1-AR subtypes and 5-HT1A receptor through a planned sequence of modifications of this molecule portion, consisting of combining a wide series of different ortho substituents or of introducing an additional or fused benzene or cyclohexane ring.1-4 The significant modulation of the affinity, activity and selectivity profile resulting form such modifications prompted us to design new WB4101 analogues, where the phenoxy moiety is b-fused to a saturated or unsaturated five-membered heterocycle, the heteroatom of the additional cycle replacing the oxygen of the removed methoxyl. Here, we report the synthesis of 6-methoxydihydroindolyl-7-oxy, 6-methoxybenzofuran-7-oxy and 6-methoxydihydrobenzofuran-7-oxy analogues of WB4101, in both the enantiomeric forms, and discuss the results of the functional and binding studies at α1-AR subtypes and 5-HT1A receptor. [1]Bolchi C. et al. Bioorg. Med. Chem. 2004, 12,4937-51. [2]Fumagalli L. et al, Bioorg. Med. Chem. 2005, 13, 2547-59. [3)Pallavicini M. et al Eur. J. Med. Chem. 2006, 4, 11025-40. [4]Pallavicini M. et al. J Med. Chem. 2006, 4, 97140-9.