title: Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits.
abstract: TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain-selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant-like activity in rats after chronic oral administration. This study determined whether TV-3326 would cause less potentiation than other irreversible MAO-inhibitors of the blood pressure (BP) response to oral tyramine in conscious rabbits. Dose-response curves were established for the increase in BP induced by tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube. From these, the dose that increased BP by 30 mmHg (ED(30)) was computed for each rabbit before and after oral administration of clorgyline, 1 mg/kg for one week, tranylcypromine 10 mg/kg, once, moclobemide, 20 mg/kg 3 times and TV-3326, 26 mg/kg for 2 weeks. Clorgyline, tranylcypromine and TV-3326 inhibited brain MAO-A by 90%; the former two inhibited intestinal MAO-A by 85-97% but TV-3326 had no effect. Tranylcypromine and clorgyline produced 6 and 20-fold increases in the pressor response to tyramine while TV-3326, like moclobemide, only potentiated it 2-fold. If TV-3326 is found to produce as little potentiation of the tyramine response in human subjects, it may be a potentially useful therapeutic agent for the treatment of Alzheimer's disease with depression.
authors.affiliation: Department of Pharmacology, Hebrew University, Hadassah Medical Centre, Ein Kerem, Jerusalem, Israel. martar@cc.huji.ac.il.
authors.forename: M
authors.initials: M
authors.lastname: Weinstock
authors.forename: E
authors.initials: E
authors.lastname: Gorodetsky
authors.forename: R H
authors.initials: RH
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Gross
authors.forename: O
authors.initials: O
authors.lastname: Weinreb
authors.forename: M B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D015078:2-Hydroxyphenethylamine / Q000494:pharmacology; D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003010:Clorgyline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066298:In Vitro Techniques; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D014191:Tranylcypromine / Q000494:pharmacology; D014439:Tyramine / Q000494:pharmacology*
chemical_list: C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D018759:Adrenergic Uptake Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D012701:Serotonin; D014191:Tranylcypromine; D015078:2-Hydroxyphenethylamine; D008995:Monoamine Oxidase; D003010:Clorgyline; D014439:Tyramine