Discovery and synthesis of novel 3-phenylcoumarin derivatives as antidepressant agents

A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.     

Synthesis and structure–activity relationship of novel cinnamamide derivatives as antidepressant agents

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure–activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b–c and 6a–b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10 mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold.     

Characteristics of depressive behavior induced by feeding thiamine-deficient diet in mice

We produced thiamine-deficient (TD) mice by TD diet treatment. The growth curve of mice on TD feeding was sharply increased until on the 10th day and subsequently the body weight gradually decreased. The mortality rate in mice was about 67% on the 30th day after the start of TD feeding. We performed the forced swimming test on the 10th and 20th day after the start of TD feeding. The duration of immobility in the forced swimming test was increased on the 20th day of TD feeding. Locomotor activity and motor co-ordination between the pair-fed control group and TD group on the 20th day of TD feeding were not significantly changed. Only a single injection of thiamine HCI (50 mg/kg, s.c.) on the 10th day after the start of a TD diet shortened the increased duration of immobility in the forced swimming test on the 20th day after the start of TD feeding. Whereas these reversal effects of thiamine treatment on the 20th day were not found when the treatment was given on the 19th day after the start of a TD diet. On the 20th day after the start of TD feeding, the increased duration of immobility time induced by TD was shortened by chronic administration of the tricyclic antidepressant imipramine (10 mg/kg, i.p.). These results suggested that behavioral changes in the forced swimming test might be involved in the degeneration of serotonergic and noradrenergic neurons.     

Synthesis,antidepressant evaluation and QSAR studies of novel 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)acetamides

In search for novel antidepressants, a series of 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)acetamides was synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Number of synthesized compounds exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (%DID). QSAR analysis was also undertaken which correlated three parameters FOSA, PISA, and glob with biological activity.     

Potential anti-depressive effects of thyrotropin releasing hormone (TRH) and its analogues

The anti-depressive effects of thyrotropin releasing hormone (TRH) and its analogues (DN-1417: gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide citrate; MK-771: L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide) were examined in behavioral despair rats, an animal model of depression. TRH, DN-1417, MK-771, amitriptyline and diazepam were injected three times after the first forced swimming. One hr after the last injection, a 5-min swimming test was performed. Experimental animals were placed in a Hall's type open-field apparatus immediately before and after the 5-min test, and their locomotor activities were determined. No significant difference was noted in the locomotor activity immediately before the 5-min test among any group. In the 5-min swimming test, TRH, DN-1417 and MK-771 caused a dose-dependent decrease in immobility, showing an anti-depressive effect similar to amitriptyline. Diazepam showed no difference compared with the control group. After the swimming test, locomotor activity remarkably decreased in the control rats, while decreased locomotor activity was partially prevented in the TRH, DN-1417, MK-771 and amitriptyline treated rats which exhibited active movement not only during the swimming period but also after it. In terms of the minimum effective dose, TRH and DN-1417 seemed to be of similar potency, while MK-771 was 40-fold stronger than TRH. An examination of a possible correlation between the cross-reactivity of TRH analogues in a radioreceptor assay and the effects of the analogues on despair rats suggested that the structure-binding relationship was proportional to the structure-activity relationship.     

Dopamine-dependent character of depressive-like behavior in WAG/Rij rats with genetic absence epilepsy

Placebo-treated WAG/Rij rats (as compared to normal Wistar rats without seizure pathology) exhibited depressive-like behavior similar to that of intact rats of the same strain: decreased exploratory activity in the open field test, increased immobility in the forced swimming test, decreased sucrose consumption and preference (anhedonia). Chronic injection of tricyclic antidepressant imipramine (15 mg/kg. i.p., for 15 days) exerted a therapeutic (antidepressant) effect on depressive-like behavior in WAG/Rij rats. After cessation of antidepressant therapy, the behavior of WAG/Rij rats didn't significantly differ from that of Wistar rats. Acute (single) injection of selective D2/D3 dopamine receptor antagonist raclopride (100 microg/kg, i.p., 15 min prior to behavioral testing) aggravated the symptoms of depressive-like behavior and suppressed antidepressant effect of chronic injection of imipramine in WAG/Rij rats, whereas it didn't exert a substantial effect on behavior of Wistar rats. Injection of D2/D3 dopamine receptor agonist Parlodel (bromocriptine) counteracted the depressive-like behavior in WAG/Rij rats and didn't exert substantial influence on behavior of Wistar rats with the exception of a decrease in immobility time in the forced swimming test. Injections of imipramine and raclopride didn't exert significant influences on the level of general locomotor activity and anxiety both in WAG/Rij and Wistar rats. The results demonstrate the dopamine-dependent character of depressive-like behavior in WAG/Rij rats, and indicate possible involvement of dopamine D2-like receptors in mediation of the antidepressant effect of imipramine on genetically determined depressive-like behavior in WAG/Rij rats.     

Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents

A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip. Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST) (another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising antidepressant lead and hence pave the way for further investigation around this chemical space.     

Effect of ACTH on the imipramine- and desipramine-induced decrease in duration of immobility time as measured in a rat forced swimming test.

In a rat forced swimming test (FS), we examined the effect of repeated injections of ACTH (adrenocorticotropic hormone) for 14 days on the decreased duration of immobility time produced by imipramine and desipramine. Both imipramine (15 and 30 mg/kg, p.o.) and desipramine (15 and 30 mg/kg, p.o.) significantly decreased the duration of immobility time in the FS. On the other hand, ACTH (100 microg/kg, i.p.) alone did not affect the duration of immobility time in FS. When ACTH (100 microg/kg, i.p.) was injected for 14 days before the 15-min swim session, it counteracted the decreased duration of immobility time induced by both imipramine and desipramine. Thus, ACTH seems to play a key role in decreasing the duration of immobility time of antidepressants in this test.     

人参总皂苷和远志总苷配伍对小鼠抗抑郁作用

目的确定人参总皂苷（GTS）和远志总苷（PTG）抗抑郁配伍剂量比例,形成参远苷（SGY）制剂,为研制开发抗抑郁新药提供实验数据。方法采用析因设计方法,GTS和PTG均选取25、50、100 mg/kg三个剂量,按照完全随机的两因素3×3实验设计,得到参远苷的9个不同配比组。C57BL/6J小鼠（用于悬尾实验）和ICR小鼠（用于强迫游泳实验）随机分为对照组、阳性药组（10 mg/kg,帕罗西汀用于悬尾实验;阿米替林用于强迫游泳实验）及参远苷的9个不同配比组,共11组。灌胃给药7 d,观察各组对悬尾或强迫游泳实验小鼠不动时间的影响,并通过空场实验观察参远苷各配比对小鼠自主活动的影响。参远苷与单味GTS、PTG的抗抑郁作用比较实验中,C57BL/6J小鼠（用于悬尾实验）和ICR小鼠（用于强迫游泳实验）随机分为对照组、阳性药组（10 mg/kg,帕罗西汀用于悬尾实验;阿米替林用于强迫游泳实验）、参远苷低中高剂量组（37.5、75、150 mg/kg）、GTS和PTG各四个剂量组（均为18.75、37.5、75、150 mg/kg）,共13组。灌胃给药7 d,观察各组对悬尾或强迫游泳实验小鼠不动时间的影响。结果析因设计结果表明,GTS和PTG之间无交互效应。参远苷配比组75 mg/kg（GTS∶PTG为50∶25）及150mg.kg-1（GTS∶PTG为100∶50）显著并稳定缩短悬尾或强迫游泳不动时间（P〈0.05）,得出GTS和PTG的剂量配伍比例为2：1。空场实验结果显示,参远苷各配比对小鼠运动总路程无影响。参远苷与单味GTS、PTG抗抑郁作用比较实验结果显示,GTS 75、150 mg/kg缩短悬尾实验小鼠不动时间（P〈0.01,P〈0.05）,对强迫游泳实验小鼠不动时间无影响。PTG 18.75、37.5 mg/kg缩短强迫游泳实验小鼠不动时间（P〈0.01,P〈0.05）,对悬尾实验小鼠不动时间无影响。参远苷75、150 mg/kg缩短悬尾实验小鼠不动时间（P〈0.05）。同时,参远苷37.5、75 mg/kg缩短强迫游泳实验小鼠不动时间（P〈0.01,P〈0.05）。结论 GTS和PTG以2：1的比例形成的参远苷（SYG）制剂,质量容易控制,作用机制多样,符合抑郁症复杂多样的发病机制,优于单味GTS和PTG,进一步研究之后,有可能成为新型的抗抑郁药物。     

Enhancement of antidepressant potency by a potentiator of AMPA receptors

1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., 5HT, NE) in prefrontal cortex at doses that are active in the forced swim test.2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility.3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine.4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.     

Antinociceptive effect of amitriptyline in mice of acute pain models

Tricyclic antidepressant drugs induce antinociceptive effect and suggest that their analgesic action could be related to the monoaminergic activity of the drugs. The analgesic activity of amitriptyline was observed in mouse models of acute pain. Mice were divided into different groups and were given amitriptyline in different doses alone and in combination with morphine. Reaction time in Hot-Plate and Tail-Flick tests was observed. Results showed that amitriptyline had antinociceptive effect in acute pain state in experimental models. Amitriptyline in combination with morphine had better analgesic effect than the morphine alone in Hot-Plate test.     

Antidepressant activity of Indian Hypericum perforatum Linn in rodents

A standardised 50% aqueous ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its antidepressant activity on various experimental paradigms of depression, viz. behavioural despair (BD), learned helplessness (LH), tail suspension (TS) and reserpine-induced hypothermia (RIH) tests in rats and mice. Pilot studies indicated that single dose administration of IHp had very little or no acute behavioural effects, hence the IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.) once daily for three consecutive days, while imipramine (15 mg/kg, i.p.), a clinically used antidepressant agent, was administered acutely to rats (CF strain, 150 +/- 10 g) and mice (Wistar strain, 23 +/- 2 g) of either sex as the standard drug. Controls animals were treated similarly with equal volume of vehicle (0.3% carboxymethyl cellulose). Indian Hypericum perforatum extract showed significant antidepressant activity on all the paradigms of depression used. Thus IHp and imipramine treatments significantly reduced the immobility time in BD and TS tests. Significant reduction in escape failures was also observed in LH test. In RIH test IHp and imipramine inhibited reserpine induced hypothermia in a dose dependent manner. The observed antidepressant activity of IHp was qualitatively comparable to that induced by imipramine.     

Antidepressant activity of hyperforin conjugates of the St. John's wort,Hypericum perforatum Linn.: an experimental study

Nine extracts of H. perforatum, containing hyperforin in conjugated forms, but devoid of free hyperforin and adhyperforin, were subjected to antidepressant screening using the forced swim test (FST). The observed activity was compared with that of SJW extracts containing hyperforin and adhyperforin (in free form). Results indicate that hyperforin conjugates exhibit significant antidepressant activity as evidenced by the reduced immobility period in the FST in rats.     

Amitriptyline-Mediated Inhibition of Neurite Outgrowth from Chick Embryonic Cerebral Explants Involves a Reduction in Adenylate Cyclase Activity

We have previously shown that amitriptyline, a tricyclic antidepressant, inhibited neurite outgrowth from chick embryonic cerebral explants, and that dibutyryl cyclic AMP, 3-isobutyl-1-methylxanthine, or theophylline can enhance neurite outgrowth from embryonic olfactory explants. In the present study, we examined the mechanism(s) underlying amitriptyline-mediated inhibition of neurite outgrowth by studying the effects of amitriptyline on adenylate cyclase activity and cyclic AMP levels. In cultured chick embryonic cerebral explants, dibutyryl cyclic AMP or theophylline, but not dibutyryl cyclic GMP, enhanced neurite outgrowth and partially reduced the inhibitory effects of amitriptyline on neurite outgrowth. Explants treated with amitriptyline for 2 days showed decreased cyclic AMP levels that significantly correlated with the degree of neurite outgrowth. Amitriptyline inhibited both basal and forskolin-stimulated adenylate cyclase activity in vitro, but only in the presence of GTP. Taken together, these data suggest that amitriptyline inhibits the activity of adenylate cyclase via a GTP-dependent mechanism, and that the subsequent decrease in cyclic AMP level may be involved in amitriptyline-mediated inhibition of neurite outgrowth.     

A gene-specific cerebral types 1, 2, and 3 RyR protein knockdown induces an antidepressant-like effect in mice

Elevation of baseline intracellular calcium levels was observed in platelets or lymphoblasts of patients with bipolar affective disorders suggesting an altered intracellular Ca(2+) homeostasis in the pathophysiology of mood disorders. The role of supraspinal endoplasmic ryanodine receptors (RyRs), which allow mobilization of intracellular Ca(2+) stores, in the modulation of depressive states was, then, investigated. Ryanodine and FK506 reduced the immobility time in the mouse forced swimming test showing an antidepressant-like profile comparable with that produced by amitriptyline and clomipramine. We generated types 1, 2, and 3 RyR knockdown mice by using selective antisense oligonucleotides (aODN) to investigate the role of each RyR isoform. A gene-specific cerebral RyR protein level reduction in knockdown animals was demonstrated by immunoblotting, immunoprecipitation, and immunohistochemical experiments. Repeated intracerebroventricular administration of aODNs complementary to the sequence of the types 1, 2, or 3 RyR produced an antidepressant-like response in the forced swimming test. The aODN-induced reduction of immobility time was temporary and reversible and did not impair motor coordination, spontaneous mobility, and exploratory activity. These findings identify cerebral RyRs as critical targets underlying depressive states and should facilitate the comprehension of the pathophysiology of mood disorders and help developing of new therapeutical strategies.     

Role of central histaminergic mechanism in behavioural depression (swimming despair) in mice

The role of the central histaminergic system in depression was studied by using swimming despair test in mice - a behavioural model of depression. In this test, immobility of mice reflects a state of depression. Intracerebral (ic) injection of histamine (50-200 micrograms) increased significantly the immobility. The H1-receptor blocker mepyramine (2.5-20 mg/kg ip) had no effect while H2-receptor blocker cimetidine (100-200 micrograms ic) caused a significant decrease in immobility. The histamine induced facilitation was blocked completely by cimetidine and antidepressant drugs-imipramine and desipramine, but remained unaffected in mice pretreated with mepyramine or atropine. The H2 agonist impromidine (20-40 micrograms ic) also enhanced significantly, the immobility which was blocked by cimetidine and antidepressant drugs. It has been concluded that central H2-receptors facilitate depression and antidepressant drugs block central H2-receptors.     

Piplartine, an amide alkaloid from Piper tuberculatum, presents anxiolytic and antidepressant effects in mice

In the present work, we studied the effects of piplartine (PIP), an amide alkaloid isolated from the roots of Piper tuberculatum (Piperaceae), in the elevated plus maze, open field, rota rod, pentylenetetrazole (PTZ)-induced seizures, and forced swimming tests, in mice (Swiss, male, 25 g) to assess anxiolytic, sedative, muscle relaxant, anticonvulsant and antidepressant effects, respectively. Results showed that PIP (50 and 100 mg/kg, i.p.), similarly to diazepam, significantly increased not only the number of entrances (100% and 66%, respectively) but also the time of permanence in the open arms (104% and 199%, respectively), indicating that PIP presents an anxiolytic activity. Both effects were completely blocked by the previous administration of flumazenil what suggests the involvement of benzodiazepine type receptors. In the open field test, although PIP did not alter the number of crossings, it significantly increased grooming (103% and 119%) and rearing (60% and 23%), at the doses of 50 and 100 mg/kg respectively, as compared to controls. However, in the rota rod test, PIP was devoid of effect. Although in the PTZ-induced convulsion test, PIP did not alter the latency time for the onset of the first convulsion, as compared to controls, it significantly reduced in 58% and 60%, respectively, the animal's latency time to death. Furthermore, a significant and dose-dependent decrease in the immobility time, as evaluated by the forced swimming test, was observed after PIP administration (41% and 75% decrease, at the doses of 50 and 100 mg/kg, respectively), suggesting an antidepressant effect, similarly to that observed with imipramine, a classical antidepressant drug used as standard. In conclusion, we showed that PIP presents significant anxiolytic and antidepressant activities, making this drug potentially useful in anxiety and depression.     

Dipeptide Mimetic of the BDNF GSB-106 with Antidepressant-Like Activity Stimulates Synaptogenesis

Dipeptide mimetic of the brain-derived neurotrophic factor bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (working name GSB-106), which reproduces the homodimeric structure of BDNF and the beta-turn of its fourth loop, activates TrkB, AKT, and ERK, exhibits neuroprotective and antidepressant activity, and is able to stimulate neurogenesis in the hippocamp of stressed mice. Using Western blot hybridization and synaptophysin (synaptogenesis marker), we showed the ability of chronically administered GSB-106 to stimulate synaptogenesis, increasing the synaptic density in the hippocamp by 50%. Under the same conditions, GSB-106 exhibited antidepressant activity (decreased (by 18%) immobility of animals in Porsolt test), which may be associated with the stimulation of neurogenesis and synaptogenesis in the hippocamp.     

The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test

Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10 mg/kg), CORT 108297 (30 mg/kg and 60 mg/kg), imipramine (10 mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60 mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.     

Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models

Herbal extracts of Hypericum perforatum L. (St. John's wort, SJW) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the antidepressive active compounds. In the present study we used the following strategy to evaluate the relative pharmacological importance of various extract components: 1. preparation of an hydroalcoholic SJW extract containing both hyperforin (3.2%) and hypericin (0.15%) (extract A); 2. step by step removal of hyperforin and hypericin led to the following extracts: Extract B, devoid of hyperforin but still containing hypericin (0.14%) and Extract C, free of hypericin and hyperforin but enriched in flavonoids ( approximately 12%). We characterized the in vivo activity profile of all three preparations using the tail suspension test (TST) in mice and the forced swimming test (FST) in rats as screening models. We further investigated the activity of pure hyperforin. Extract B and C (500 mg/kg each) as well as pure hyperforin (8 mg/kg) significantly shortened immobility time in the TST after acute pre-treatment whereas extract A was inactive. In the FST all three extracts decreased immobility time in a dosage of 500 mg/kg after acute as well as after repeated treatment. The present results clearly show that an SJW extract free of hyperforin and hypericin exerts antidepressant activity in behavioral models, supporting our working hypothesis that flavonoids are part of the constituents responsible for the therapeutic efficacy of SJW extracts. We also could show that hyperforin contributes to the beneficial properties of SJW extract, confirming the hypothesis that the crude SJW extract contains several constituents with antidepressant activity.