Potential antidepressant properties of IDN 5491 (hyperforin-trimethoxybenzoate), a semisynthetic ester of hyperforin.
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.
Cervo
Luigi
L
Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. cervo@marionegri.it
Mennini
Tiziana
T
Rozio
Marco
M
Ekalle-Soppo
Charlotte Blanche
CB
Canetta
Alessandro
A
Burbassi
Silvia
S
Guiso
Giovanna
G
Pirona
Lorenza
L
Riva
Antonella
A
Morazzoni
Paolo
P
Caccia
Silvio
S
Gobbi
Marco
M
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*
D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D004952:Esters; D010936:Plant Extracts; D013729:Terpenes; C455161:hyperforin trimethoxybenzoate; D010696:Phloroglucinol; C001654:hyperforin