title: Vasoactive properties of antidepressant N-alkyl derivatives.
abstract: 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.
authors.affiliation: Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN Av. IPN 2508, Zacatenco, México.
authors.forename: Renata
authors.initials: R
authors.lastname: Sánchez-Ortiz
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez-Alvarez
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Bobadilla Lugo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D007099:Imipramine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008745:Methylation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D005473:Fluoxetine; D007099:Imipramine; D017367:Selective Serotonin Reuptake Inhibitors