title: Potential antidepressant properties of IDN 5491 (hyperforin-trimethoxybenzoate), a semisynthetic ester of hyperforin.
abstract: Hyperforin is one of the possible active principles mediating the antidepressant activity of Hypericum perforatum L. extracts. The ester derivative IDN 5491 (hyperforin-trimethoxybenzoate) showed antidepressant-like properties in the forced swimming test (FST) in rats, with no effect on open-field activity, when given as three intraperitoneal injections in 24 h at 3.125 and 6.25 mg/kg. The plasma concentrations of IDN 5491 were 30-50 microM, and those of hyperforin much lower but still close to those after effective doses of hyperforin-dicyclohexylammonium and Hypericum extract. This suggests that hyperforin plays a role in the antidepressant-like effect of the ester and of Hypericum extract. In vitro binding and uptake data showed that IDN 5491 is inactive on a wide panel of CNS targets at a concentration (14 microM) much higher than that measured in the brain of treated rats (0.3 microM). Like the extract, the antidepressant-like effect of IDN 5491 was blocked by (-)-sulpiride, a selective D2 receptor antagonist and by BD-1047, a selective sigma1 antagonist. Ex-vivo binding studies showed that brain sigma1 receptors are occupied after in vivo treatment with IDN 5491, possibly by an unknown metabolite or by endogenous ligand induced by hyperforin.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. cervo@marionegri.it
authors.forename: Luigi
authors.initials: L
authors.lastname: Cervo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Marco
authors.initials: M
authors.lastname: Rozio
authors.forename: Charlotte Blanche
authors.initials: CB
authors.lastname: Ekalle-Soppo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Canetta
authors.forename: Silvia
authors.initials: S
authors.lastname: Burbassi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pirona
authors.forename: Antonella
authors.initials: A
authors.lastname: Riva
authors.forename: Paolo
authors.initials: P
authors.lastname: Morazzoni
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000627:therapeutic use*; D004952:Esters; D020902:Hypericum; D007103:Immobilization; D008297:Male; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D010936:Plant Extracts / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D013312:Stress, Physiological / Q000188:drug therapy / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D004952:Esters; D010936:Plant Extracts; D013729:Terpenes; C455161:hyperforin trimethoxybenzoate; D010696:Phloroglucinol; C001654:hyperforin