Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3β inhibitors with in vivo antidepressant activity

Recent findings of potential implications of glycogen synthase kinase-3β (GSK-3β) dysfunction in psychiatric disorders like depression, have increased focus for development of GSK-3β inhibitors with possible anti-depressant activity. Keeping this in view, we synthesized a series of benzimidazole-linked-1,3,4-oxadiazole carboxamides and evaluated them for in vitro GSK-3β inhibition. Active compounds were investigated for in vivo antidepressant activity in Wistar rats. Docking studies of active compounds have also been performed. Among nineteen compounds synthesized, compounds 7a, 7r, 7j, and 7d exhibited significant potency against GSK-3β in sub-micromolar range with IC₅₀ values of 0.13 μM, 0.14 μM, 0.20 μM, 0.22 μM respectively and significantly reduced immobility time (antidepressant-like activity) in rats compared to control group. Docking study showed key interactions of these compounds with GSK-3β. These compounds may thus serve as valuable candidates for subsequent development of effective drugs against depression and related disorders.     

2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity

Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (sc 60 mg/kg).     

A new synthesis of 4′-resveratrol esters and evaluation of the potential for anti-depressant activity

The 4′-ester analog of the disease preventative resveratrol 1 (RV), 4′-acetyl-RV 2 along with 4′-pivaloate 13 and benzoate 14 RV were synthesized. The previously developed palladium catalyzed decarbonylative Heck coupling was used to assemble the stilbene core together with 3,5-dibenzyl protected phenol intermediates that allowed for efficient coupling and deprotection using boron trifluoride etherate. Studies with Long-Evans rats were performed to establish safety, toxicity, and behavioral parameters. In addition, the Porsalt forced-swim test was used to demonstrate anti-depressant activity.     

Screening of chalcone analogs with anti-depressant,anti-inflammatory,analgesic, and COX-2-inhibiting effects

A group of 2-methyl-4-phenylquinoline-chalcone analogs (2a–2x) was synthesized and investigated for anti-depressant, anti-inflammatory, and analgesic effects as cyclooxygenase-2 inhibitors. Pharmacological experiments identified 24 analogs that exhibited anti-depressant, anti-inflammatory, and analgesic activities. In particular, compounds 2c, 2k, and 2w markedly shortened immobility times and exhibited the most anti-depressant activity. In addition, the mechanisms of action of the analogs 2c, 2k, and 2w were likely related to increased serotonin levels in the central nervous system. Compounds 2c, 2k, and 2w displayed reasonable cyclooxygenase-2 inhibitory effects (IC₅₀ values from 0.21 to 0.29 µmol/L) similar to celecoxib (IC₅₀: 0.19 µmol/L) in vitro. A molecular docking study of compound 2k also was conducted.     

Evaluation of anti-depressant-like activity of linezolid, an oxazolidinone class derivative - an investigation using behavioral tests battery of depression

Linezolid, an oxazolidinone class derivative is a reversible and nonselective inhibitor of monoamine oxidase (MAO), predominantly for MAO-A type. MAO-A is a key enzyme regulating the catabolism of catecholamine neurotransmitters in the brain. It is well known that the catecholaminergic neuronal systems are associated with depression and inhibition of MAO-A level in the brain could be used to treat depression. Hence, the objective of this study was to evaluate the anti-depressant-like effect of linezolid, a MAO-A inhibitor in the animal models of depression. In the present study, linezolid (10 & 20 mg/kg, i.p.), exhibited anti-depressant-like effects in forced swim test (FST) and tail suspension test (TST) in mice without influencing the baseline locomotion. Moreover, linezolid (10 & 20 mg/kg, i.p.), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and antagonized the reserpine-induced hypothermia in rats. In conclusion, the behavioral investigation revealed the anti-depressant-like effect of linezolid in rodent’s behavioral model.     

Rapid clinical effectiveness of MIF-I in the treatment of major depressive illness

A double-blind 28 day study was conducted to compare the anti-depressant efficacy of MIF-I with that of imipramine. Twenty patients hospitalized with major depressive illness participated. Clinical responses were measured by using the Hamilton Depression Rating Scale, the Global Severity of Illness Scale, the Zung Self-Rating Depression Scale as well as the 100 mm line self-rating for depression. The results indicate that MIF-I was at least as effective as imipramine in this study, and that its anti-depressive effect was a rapid and often dramatic one.     

Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3 mg/kg, q.d.).