Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia

In search of a uroselective alpha (1A) subtype selective antagonist, a nove l series of 6-OMe hexahydrobenz [e]isoindoles attached to a bicyclic hetero cyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,l th is bicyclic series has very specific requirements for the heterocyclic atta chments. The most important structural features contributing to the alpha ( 1A)/alpha (1B) selectivity of these compounds were identified. In vitro fun ctional assays for the al adrenoceptor subtypes were used to further charac terize the most selective compounds, and in vivo models of vascular vs pros tatic tone were used to assess uroselectivity. Compound 48 showed the highe st degree of selectivity in the radioligand binding assays (56-fold), in th e in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).