THE FUROXAN SYSTEM AS A USEFUL TOOL FOR BALANCING HYBRIDS WITH MIXED ALPHA(1)-ANTAGONIST AND NO-LIKE VASODILATOR ACTIVITIES

The design of new vasodilator derivatives in which two different pharmacophoric groups are present in a single molecule has been pursued by substitution of NO-prodrug furoxan moieties for the furanylcarbonyl function in Prazosin, a well-known alpha(1)-receptor antagonist. The aim was to obtain new antihypertensive agents in which two vasodilation mechanisms, alpha(1)-antagonist and NO-mediated, can operate in an appropriate balance. The alpha(1)-antagonist activity was assessed on rat aortic strips in the presence and in the absence of oxyhemoglobin (HbO(2)), a well-known scavenger of nitric oxide. The resulting hybrids displayed different pharmacological behaviors. When the 4-furoxanylcarbonyl system, bearing an ester or an amide function at; the 3-position, was present (derivatives 7a,b), hybrids with predominant al-antagonist activity were obtained. By contrast, in the derivative 7c, in which the nitrile function is linked to the 3-position of the furoxan ring, the NO-mediated vasodilating properties are predominant. Finally, the (furoxanylsulfonyl)piperidine derivatives 13a,b showed NO vasodilation and alpha(1)-antagonist activities in an appropriate balance. For the furoxan derivatives, the NO-dependent vasodilating ability, assessed on the K+-depolarized aortic strip, and the NO release features under the action of thiol cofactors are also discussed.