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

α1-Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of α1-adrenoceptor subtypes. We synthesized and studied the α1-adrenoceptor blocking properties of new molecules structurally related to the α1B-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 α1B over α1A, while maintaining a similar selectivity for the α1B-adrenoceptor relative to the α1D-adrenoceptor. Compound (+)-3 may represent a useful tool for α1B-adrenoceptor characterization in functional studies.

Compound (+)-3, R = CH3, improved the functional α1B-adrenoceptor selectivity of (+)-cyclazosin.Figure optionsDownload as PowerPoint slide