Specific modulation of sigma binding sites by the anxiolytic drug opipramol

Abstract

The atypical anxiolytic and antidepressive drug opipramol binds with high affinity to sigma1 and somewhat lower affinity to sigma2 sites. After subchronic treatment, opipramol significantly down-regulated sigma2 but not sigma1 sites. This effect was not seen for imipramine, citalopram, and reboxetine under similar conditions. On the other hand, only imipramine reduced the number of sigma1 sites. It is suggested that effects at sigma2 sites are involved in the anxiolytic properties of opipramol.

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration–motor neuron disease

“…We used 3 Sigma‐1 ligands, AC915 (N‐(2‐(3,4‐dichlorophenyl)acetoxy)‐ethylpyrrolidine (specific Sigma‐1 antagonist),32 haloperidol (Sigma‐1 antagonist),33 and opipramol (specific Sigma‐1 agonist)34 to determine whether these small molecules can mimic the effect of altered expression of SIGMAR1 on TDP‐43 subcellular localization (see Fig 4D). We observed that both AC915 and opipramol had a significant effect on TDP‐43 localization, whereby 50nM of AC915 (antagonist) or 15nM of opipramol (agonist) significantly decreased (1.5‐fold, p = 0.038) or increased (1.5‐fold, p = 0.020), respectively, the relative level of TDP‐43 in the cytoplasm compared with untreated cells.…”

Neuropharmacology of the Anxiolytic Drug Opripramol, a Sigma Site Ligand

“…With opipramol no dose-dependency became apparent between 10, 20 and 40 mg/kg. In a modified design of the forced swim test (9 days of treatment) we also observed a reduced immobility time for 20 mg/kg opipramol daily, but the effect was less pronounced than following a comparable treatment with the antidepressants reboxetine or citalopram [15]. The relationship between in vitro IC50 values (half-maximum inhibitor concentrations) for sigma binding (nmol/l) and ex vivo ED50 values (oral doses which occupy sigma sites by 50 % one hour after administration) (mg/kg body weight) for opipramol and some other sigma ligands.…”

“…Imipramine, in contrast, caused no reduction of sigma tot or sigma 2 receptor densities, but a weak reduction of sigma 1 receptor densities by 16 % compared to control. Neither of the treatment led to any relevant change in the affinities of either radioligand [15].…”

Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders

“…Opipramol is a high-affinity Sig-1R agonist with weak affinities for H 1 , sigma-2, 5-HT 2 , and D 2 receptors. Opipramol lacks affinities for serotonin and noradrenalin reuptake sites[99]. Opipramol is effective in treatment of depressive mood, somatization, anxiety, and sleep disturbance[100].…”