(+)-Cyclazosin Derivatives as α1-Adrenoceptor Antagonists

Abstract

The prazosin-related compound (+)-cyclazosin [(+)-1] is an α 1 -adrenoceptor antagonist with moderate selectivity for the α 1 b -adrenoceptor subtype (selectivity ratio: α 1 b /α 1 a = 90, α 1 b /α 1 d = 24). To improve its pharmacological profile, the novel chiral derivatives (+)-2-(+)-5, bearing a bromo, a methyl, a methoxy or an acetyl group in position 5 of the 2-furoyl moiety, were synthesized and evaluated for their α 1 -adrenoceptor blocking activity. All the compounds displayed, like (+)-1, high and preferential affinity for the α 1 b -adrenoceptor in binding and functional assays. Interestingly, in functional assays, compounds (+)-3 and (+)-4 showed, in comparison with (+)-1, an increase in the α 1 B /α 1 A selectivity (407 and 724 vs. 44), whereas compound (+)-5 exhibited an improved α 1 B / α 1 D selectivity (1513 vs. 138).