Thirty
compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl)
acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds
having N′-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide
skeleton were synthesized and evaluated as monoamine oxidase (MAO)
inhibitors. All of the compounds exhibited selective MAO-A inhibitor
activity in the nanomolar or low micromolar range. The results of
the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008
μM, Selectivity Index (SI): 9.70 × 10–4), 7 (0.009 μM, SI: 4.55 × 10–5), 14 (0.001 μM, SI: 8.00 × 10–4), 21 (0.009 μM, SI: 1.37 × 10–5), and 42 (0.010 μM, SI: 5.40 × 10–6), exhibiting the highest inhibition and selectivity toward hMAO-A
and nontoxic to hepatocytes were assessed for antidepressant activity
as acute and subchronic in mice. All of these five compounds showed
significant antidepressant activity with subchronic administration
consistent with the increase in the brain serotonin levels and the
compounds crossed the blood–brain barrier according to parallel
artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A
profile, which is highly consistent with the in vitro data.
In 2008, the Food and Drug Administration of the US issued a warning about the neuropsychiatric side effects of montelukast. Previous clinical studies on montelukast have reported conflicting results and, to the best of our knowledge, no experimental studies concerning these side effects had been conducted. In the current study, the effect of montelukast on depression-like behavior in an ovalbumin (OVA)-induced mouse model was investigated. A total of 3 OVA challenges were applied at 2 week intervals for the persistence of asthma. Depression-like behavior was assessed using forced swim tests following each challenge and locomotor activities were evaluated using open field tests. At the end of the current study, plasma montelukast concentrations were measured and the development of asthma and effect of montelukast treatment were histopathologically examined. Inflammation scores that were increased in the OVA mice following all challenges were indicated to be reduced by montelukast treatment. The immobility time of mice increased beginning with the first challenge and this was also reduced by montelukast treatment. Montelukast administration to the control mice did not alter immobility times. Moreover, motor activity of the OVA and montelukast-treated mice were not altered. The results indicated there was no association between chronic montelukast treatment and depression. Furthermore, the chronic administration of montelukast to non-asthmatic mice did not increase immobility. However, depressive behavior increased at all time points in the OVA mice. These results indicated that chronic montelukast treatment is not associated with depression-like behavior and confirmed the association between asthma and depression. Further studies are required to provide an improved understanding of the neuropsychiatric side effects of montelukast.
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