(+)-Igmesine hydrochloride

IC50: 19.1 nM

JO 1784 is a selective σ1 receptor ligand.

The CNS σ receptor ligands, as is known, modulates central neurotransmitter systems ( noradrenergic-, glutaminergic-, and dopaminergic-neurons was included).

In vitro: Compared with control, data obtained displayed significant reduction in the densities of β-adrenergic, but not σ1, 5-HT1A, and GABAB receptors in fluoxetine (18%), desipramine (DMI, 32%) and JO 1784 (20%)-treated groups. Tyrosine hydroxylase (TH) activity was significantly (30–32%) decreased in all treated groups. Further, fluoxetine and DMI excluding the JO 1784 -treated groups diaplayed 85 and 40% reductions in serotonin (5-HT) and noradrenaline (NE) neuronal uptake, respectively. Following acute treatment, JO 1784 is inactive for monoamine oxidase (MAO) A or B [1].

In vivo: In vivo studies, JO 1784 at behaviorally active doses exhibited weak effects on the NE uptake but has no activity in altering 5-HT and DA synthesis or antagonizing selective drug-stimulated depletion of monoamine neuronal uptake. NMDA-induced potentiates cGMP was inhibited by JO 1784, indicating that JO 1784 may interfere with the NMDA receptor/NOS/cGMP pathway. Although it appears that the pharmacological actions of JO 1784 partially is modulated by the monoaminergic system, there is still need to find other possible mechanisms of antidepressant action [1].

Clinical trial: So far, no clinical study has been conducted.

Reference:
[1].  Akunne HC, Zoski KT, Whetzel SZ, Cordon JJ, Brandon RM, Roman F, Pugsley TA. Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant. Neuropharmacology. 2001 Jul;41(1):138-49.

The sigma receptor ligand JO 1784 (igmesine hydrochloride) is neuroprotective in the gerbil model of global cerebral ischaemia.[Pubmed:7498313]

Eur J Pharmacol. 1995 Sep 5;283(1-3):217-25.

To assess the effects of the novel sigma receptor ligand JO 1784 ((+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride or igmesine hydrochloride) on behavioural and histological changes following cerebral ischaemia, the gerbil model of cerebral ischaemia was used. Two experiments were carried out. In the first animals were either sham operated, subjected to 5 min of bilateral carotid occlusion or administered JO 1784 (25, 50, 75 or 100 mg/kg p.o.) 1, 24 and 48 h after 5 min bilateral carotid occlusion and histological evaluation carried out 96 h after surgery. In the second experiment the effects of JO 1784 administered at a dose of 100 mg/kg i.p. 30 min, 6, 24 and 48 h post-surgery on home cage activity and nitric oxide (NO) synthase activity in the cortex, hippocampus, cerebellum and brain stem 4 days after surgery was examined. Extensive neuronal death was observed in the CA1 region of 5 min occluded animals. JO 1784 (50, 75 and 100 mg/kg) provided significant protection against this ischaemia-induced cell death (P < 0.03-0.005). In the second experiment a large increase in home cage activity was observed for 5 min occluded animals for 12 h after surgery (P = 0.0018-0.02). A large increase in NO synthase activity was observed in all brain regions for 5 min occluded animals. Post-administration of JO 1784 attenuated the ischaemia-induced hyperactivity and increased NO synthase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant.[Pubmed:11445194]

Neuropharmacology. 2001 Jul;41(1):138-49.

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.