HETEROARYLOXY ANALOGUES OF WB4101: SYNTHESIS AND BIOLOGICAL EVALUATION AT ALPHA-1-ADRENOCEPTOR SUBTYPES

The physiological role of the three alpha-1-adrenoceptors subtypes (alpha-1A, alpha-1B, alpha-1D) has been intensively investigated in recent years as well as their involvement in pathological disorders, in particular in hypertension and il lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).Our research group has long been involved in designing new alpha-1-AR lignads structurally related to 2-(2,6-dimethoxyphenoxy)ethylaminomethyl-1,4-benzodioxane (WB4101), a potent alpha-1 antagonist with a slight selectivity for alpha-1A and, to a minoe extent, for alpha-1D-ARs with respect to alpha-1B-AR and 5-HT1A serotoninergic receptor. More recently, we have extensively investigated the role of the phenoxy moiety of WB4101 in the interaction with alpha-1-AR subtypes and 5HT1A 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. The significant mdulation of the affinity, activity and selectivity profile resulting from such modificatons prompted us to design new WB4101 analogues, where the phenoxy moiety is b-fused to a saturated or unsaturated five membered heterocycle, the heteroarom 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 alpha-1-AR subtypes and 5-HT1A receptor.