Curcumin analogues inhibit phosphodiesterase-5 and dilate rat pulmonary arteries.
J Pharm Pharmacol
; 67(1): 87-95, 2015 Jan.
Article
en En
| MEDLINE
| ID: mdl-25176340
ABSTRACT
OBJECTIVES:
Phosphodiesterase (PDE)-5 inhibitors are useful as vasodilators for the treatment of pulmonary arterial hypertension. We aimed to study curcumin analogues for PDE5 inhibitory activity and vasorelaxation of rat pulmonary arteries.METHODS:
Three natural curcuminoids (1-3) and six synthetic analogues (4-9) were tested for PDE5 and PDE6 inhibitory activities using enzymatic radioassay. Their vasorelaxation was measured using freshly isolated segments of rat pulmonary artery and aorta. KEYFINDINGS:
Curcuminoids (1-3) mildly inhibited PDE5 (half maximal inhibitory concentration (IC50 ) = 18 µm) the metamethoxyl of curcumin was important for PDE5 inhibition. But hydroxyl rearrangements, removing both methoxyls and one ketomethylene, yielded the potent 7 and 9 (IC50 = 4 µm) (compared with sildenafil, IC50 = 0.03 µm). Only 1, 3 and 4 were PDE5 selective over PDE6. Triazole-carboxylic addition provided water-solubility while preserving potency. All analogues possessed concentration-dependent vasorelaxant activity on pulmonary arteries (40% of maximal effective concentration (EC40 ) = 29-90 µm, maximum response = 60-90% at 300 µm), while compounds (1-8) were weakly acting in aorta (maximum response <40%). Only demethoxycurcumin (2) and analogues 5, 8, 9 had endothelium-dependent actions. Sildenafil was highly potent (EC40 = 0.04 µm) and highly endothelium dependent in pulmonary artery but weak on intact aorta (EC40 = 1.8 µm). Activity profiles suggest actions through additional cell pathways for promoting vasorelaxation.CONCLUSIONS:
Curcumin analogues are potential leads for developing efficacious and selective PDE5 inhibitors and other pathologies of pulmonary hypertension.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Arteria Pulmonar
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Vasodilatadores
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Curcumina
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Inhibidores de Fosfodiesterasa 5
Límite:
Animals
Idioma:
En
Revista:
J Pharm Pharmacol
Año:
2015
Tipo del documento:
Article
País de afiliación:
Tailandia