Synthesis and alpha1-adrenoceptor antagonist activity of derivatives and isosters of the furan portion of (+)-cyclazosin

Alpha1-adrenoceptor selective antagonists are crucial in investigating the role and biological functions of alpha1-adrenoceptor subtypes. We synthesized and studied the a1-adrenoceptor blocking properties of new molecules structurally related to the alpha1B-adrenoceptor selective antagonist (+)-cyclazosin, in an attempt to improve its receptor selectivity. In particular, we investigated the importance of substituents introduced at position 5 of the 2-furan moiety of (+)-cyclazosin and its replacement with classical isosteric rings. The 5-methylfuryl derivative (+)-3, [(+)-metcyclazosin], improved the pharmacological properties of the progenitor, displaying a competitive antagonism and an 11 fold increased selectivity for alpha1B over alpha1A, while maintaining a similar selectivity for the alpha1B-adrenoceptor relative to the alpha1D adrenoceptor. Compound (+)-3 may represent a useful tool for alpha1B adrenoceptor characterization in functional studies.