Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant.
Igmesine is a selective sigma (sigma(1)) ligand that was reported to exert antidepressant action through an unknown mechanism of action. A number of neurochemical measures were taken in this study in efforts to understand its mode of action. Following 21-day drug treatments, the actions of igmesine on a number of neurochemical measures were investigated. Data obtained showed significant decreases in the densities of beta-adrenergic but not 5-HT(1A), sigma(1) and GABA(B) receptors in fluoxetine (18%), desipramine (DMI, 32%) and igmesine (20%)-treated groups when compared with control. Tyrosine hydroxylase (TH) activity was significantly (30-32%) reduced in all treated groups. Further, fluoxetine and DMI excluding the igmesine-treated groups showed 85 and 40% reductions in serotonin (5-HT) and noradrenaline (NE) neuronal uptake, respectively. Following acute treatment, igmesine lacked activity for monoamine oxidase (MAO) A or B (IC(50)>10 microM). In in vivo studies, at behaviorally active doses, igmesine showed weak effects on the NE uptake but lacked activity in altering 5-HT and DA synthesis or antagonizing selective drug-induced depletion of monoamine neuronal uptake. N-methyl-D-aspartate (NMDA)-induced increases in cGMP was blocked by igmesine indicating that igmesine may interfere with the NMDA receptor/nitric oxide synthase/cGMP pathway. Although it appears that part of the pharmacological actions of igmesine is mediated by the monoaminergic system, there is still need to explore other possible mechanisms of antidepressant action.
Akunne
H C
HC
CNS Pharmacology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. hyacinth.akunne@pfizer.com
Zoski
K T
KT
Whetzel
S Z
SZ
Cordon
J J
JJ
Brandon
R M
RM
Roman
F
F
Pugsley
T A
TA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D019329:Idazoxan / Q000494:pharmacology; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D002934:Cinnamates; D003521:Cyclopropanes; D011943:Receptors, Adrenergic, beta; D018080:Receptors, GABA-B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; C065310:igmesine; D019329:Idazoxan