TY - JOUR
T1 - Vasoactive properties of antidepressant N-alkyl derivatives
AU - Sánchez-Ortiz, Renata
AU - Pérez-Álvarez, Víctor
AU - Bobadilla Lugo, Rosa A.
PY - 2007
Y1 - 2007
N2 - Hypotension is a principal side effect of antidepressant therapy. In addition to serotonin and noradrenalin reuptake inhibition, some antidepressants have shown ion channel interactions which are thought to be related to the vascular effects of these agents. Methylation of the pharmacophore has shown to change the pharmacological properties of a variety of compounds. The purpose of this work was to evaluate whether methylation of the amino group of imipramine (TCA's) and fluoxetine (SSRI) could change their vasodilator properties. N-methyl imipramine (NMI), N-methyl fluoxetine and (NMF) N-N dimethyl fluoxetine (NNDF) were synthesized and compared with desipramine (DES), imipramine (IMI) and fluoxetine (F) in their ability to relax rat aortic rings pre-contracted with 80mM KCl using an isolated bath preparation. Drugs were evaluated in thoracic aorta rings with and without endothelium. All compounds displayed a vasorelaxant effect. Endothelium-denuded aortic rings showed an increased relaxant response for IMI and derivatives compared with endothelium-intact vessels, while no endothelium-dependent effect was observed with F and its methyl derivatives. Maximal relaxant potency was displayed by dimethylated derivatives (IMI and NMF), while NMI in the TCA series and NNDF in the SSRI series (both with 3 methyl groups), had the least potency to relax either preparation. Endothelium plays an important role inhibiting the vasodilatation induced by IMI and its derivatives. Vascular relaxation is increased in the compounds tested with 2 methyl groups in their structure, while the presence of 3 methyl groups (positive charge) importantly reduced the relaxant potency.
AB - Hypotension is a principal side effect of antidepressant therapy. In addition to serotonin and noradrenalin reuptake inhibition, some antidepressants have shown ion channel interactions which are thought to be related to the vascular effects of these agents. Methylation of the pharmacophore has shown to change the pharmacological properties of a variety of compounds. The purpose of this work was to evaluate whether methylation of the amino group of imipramine (TCA's) and fluoxetine (SSRI) could change their vasodilator properties. N-methyl imipramine (NMI), N-methyl fluoxetine and (NMF) N-N dimethyl fluoxetine (NNDF) were synthesized and compared with desipramine (DES), imipramine (IMI) and fluoxetine (F) in their ability to relax rat aortic rings pre-contracted with 80mM KCl using an isolated bath preparation. Drugs were evaluated in thoracic aorta rings with and without endothelium. All compounds displayed a vasorelaxant effect. Endothelium-denuded aortic rings showed an increased relaxant response for IMI and derivatives compared with endothelium-intact vessels, while no endothelium-dependent effect was observed with F and its methyl derivatives. Maximal relaxant potency was displayed by dimethylated derivatives (IMI and NMF), while NMI in the TCA series and NNDF in the SSRI series (both with 3 methyl groups), had the least potency to relax either preparation. Endothelium plays an important role inhibiting the vasodilatation induced by IMI and its derivatives. Vascular relaxation is increased in the compounds tested with 2 methyl groups in their structure, while the presence of 3 methyl groups (positive charge) importantly reduced the relaxant potency.
UR - http://www.scopus.com/inward/record.url?scp=48249108750&partnerID=8YFLogxK
M3 - Artículo
SN - 0083-8969
VL - 50
SP - 93
EP - 94
JO - Proceedings of the Western Pharmacology Society
JF - Proceedings of the Western Pharmacology Society
ER -