Studies on Agents with Mixed NO-Dependent Vasodilating and β-Blocking Activities

Abstract

Purpose. A series of derivatives having a propranolol-like moiety linked to NO-donor furoxan substructures were synthesized. The main objective of this investigation was to obtain agents with mixed NO-dependent vasodilating and β-blocking activities.

Methods. Most of the target compounds were synthesized from the appropriate furoxans bearing XCH₂CH₂NH₂ (X = O, S, SO₂) chains at the 4 position of the ring, using A1(C₂H₅)₃ in methylene chloride solution and (±)2,3-epoxypropyl 1-naphtyl ether. Two of the final products (X = CONH) were obtained by coupling the appropriate furoxancarboxylic acids with N-[2-hydroxy-3-(l-naphthoxy)propyl]-ethylenediamine. β₁- and β₂-blocking activities were examined on isolated guinea pig right atria and on guinea pig trachea respectively. Vasodilating properties were assessed on endothelium denuded strips of rat aorta.

Results. Some derivatives behave as well balanced 'hybrids' displaying NO-dependent vasodilating and β-blocking properties in the same concentration range. Some others display either prevalent β-blocking or vasodilating activity. Generally speaking hybrid formation lowers the affinity for β-receptors, in particular for β₂-type, to give an increase in β₁/β₂ selectivity.

Conclusions. The furoxan system is a flexible tool in designing analogues of propranolol whose NO-donating and β-blocking properties are modulated over a wide range.