(+)-Cyclazosin Derivatives as alpha1-Adrenoceptor Antagonists

The prazosin-related compound (+)-cyclazosin [(+)-1] is an α1-adrenoceptor antagonist with moderate selectivity for the α1b-adrenoceptor subtype (selectivity ratio: α1b/α1a 90, α1b/ α1d = 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 α1b-adrenoceptor blocking activity. All the compounds displayed, like (+)-1, high and preferential affinity for the α1b-adrenoceptor in binding and functional assays. Interestingly, in functional assays, compounds (+)-3 and (+)-4 showed, in comparison with (+)-1, an increase in the α1B/α 1A selectivity (407 and 724 vs. 44), whereas compound (+)-5 exhibited an improved α1B/α1D selectivity.