Synthesis and α1-adrenoceptor antagonist activity of derivatives and isosters of the furan portion of (+)-cyclazosin

Abstract α 1 -Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of α 1 -adrenoceptor subtypes. We synthesized and studied the α 1 -adrenoceptor blocking properties of new molecules structurally related to the α 1B -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 α 1B over α 1A , while maintaining a similar selectivity for the α 1B -adrenoceptor relative to the α 1D -adrenoceptor. Compound (+)- 3 may represent a useful tool for α 1B -adrenoceptor characterization in functional studies.