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 (HbO2), 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 alpha 1-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.
Department of Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Facoltà' di Farmacia, Italy.
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Fruttero
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Boschi
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Di Stilo
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Gasco
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta; D003545:Cysteine / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D010108:Oxyhemoglobins / Q000494:pharmacology; D011224:Prazosin / Q000031:analogs & derivatives / Q000138:chemical synthesis; D051381:Rats; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D010069:Oxadiazoles; D010108:Oxyhemoglobins; D014665:Vasodilator Agents; C010166:furoxans; D009569:Nitric Oxide; D003545:Cysteine; D009638:Norepinephrine; D011224:Prazosin