|Year : 2015 | Volume
| Issue : 2 | Page : 103-108
Pharmacological evaluation of novel 5-HT 3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery
Deepali Gupta, Mahesh Radhakrishnan, Devadoss Thangaraj, Yeshwant Kurhe
Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India
|Date of Submission||04-Sep-2013|
|Date of Decision||14-Dec-2013|
|Date of Acceptance||17-May-2014|
|Date of Web Publication||1-Apr-2015|
Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: In the last few decades, serotonin type-3 (5-HT 3 ) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT 3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT 3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery. Materials and Methods: Mice were given QCM-13 (2 and 4 mg/kg, intraperitoneally [i.p.]) or diazepam (2 mg/kg, i.p.) or vehicle and after 30 min, mice were subjected to four validated behavioral test batteries viz. elevated plus maze, hole board, light-dark and open field tests. Interaction study of QCM-13 with m-chlorophenyl piperazine (mCPP) (mCPP, a 5-HT 2A/2C receptor agonist, 1 mg/kg, i.p.) and buspirone (BUS, a partial 5-HT 1A agonist, 10 mg/kg, i.p.) were performed to assess the pharmacological mechanism of the drug. Results: QCM-13 expressed potential anxiolytic effect with significant (P < 0.05) increase in behavioral parameters measured in aforementioned preliminary models. Besides, QCM-13 was unable to reverse the anxiogenic effect of mCPP, but potentiated anxiolytic affect of BUS. Conclusion: The results suggest that QCM-13 can be a potential therapeutic candidate for the management of anxiety-like disorders and combination doses of novel 5-HT 3 receptor antagonist with standard anxiolytics may improve therapeutic efficacy.
Keywords: 5-HT 3 receptor antagonist, antianxiety activity, QCM-13
|How to cite this article:|
Gupta D, Radhakrishnan M, Thangaraj D, Kurhe Y. Pharmacological evaluation of novel 5-HT 3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery. J Pharm Bioall Sci 2015;7:103-8
|How to cite this URL:|
Gupta D, Radhakrishnan M, Thangaraj D, Kurhe Y. Pharmacological evaluation of novel 5-HT 3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery. J Pharm Bioall Sci [serial online] 2015 [cited 2021 Feb 27];7:103-8. Available from: https://www.jpbsonline.org/text.asp?2015/7/2/103/154429
Serotonin is a biogenic amine biochemically derived from the tryptophan, plays an important role as a neurotransmitter in the monoaminergic pathways. Originating from raphe nuclei, it provides an intense and widespread innervation of corticolimbic structures such as frontal cortex, septum, amygdala and hippocampus, the central areas for controlling mood and emotional behavior. ,, Thus, disturbances in the activity of serotonergic system may lead to mood disorders such as anxiety, depression and other comorbid disorders causing significant personal distress, reduced "quality of life," increased morbidity and mortality as well as a significant economic burden on an individual. 
Apart from serotonin reuptake inhibitors, serotonin transporters and neurotransmission modulators, extensive research have proven the involvement of serotonin receptors agonists/antagonists (at the molecular level, including more or less all types of 5-HT receptors and their sub-types) acting on both pre (5-HT 1B) as well as postsynaptic (5-HT 1, 5-HT 2, 5-HT 4, 5-HT 5-7 ) receptors in one or another form of anxiety disorder. Thus, the contribution of serotonin type-3 receptor and sub-types in the management of psychological disorders is quite significant. 
The pharmacological activity of various drugs with 5-HT 3 receptor antagonistic activity has also been evaluated for generalized anxiety disorders or comorbid anxieties, which are being commercially available for nonpsychological disorders such as antiemetics, prokinetics.  In example, ondansetron, a 5-HT 3 receptor antagonist, is studied for the management of depression and anxiety. , Though some contradictory results are observed for its anxiolytic activity it has been found effective both in humans as well as in rodents. ,, Other 5-HT 3 antagonists such as tropisetron, granisetron, ricasetron, and zacopride have also been reported as potent anxiolytic agents. ,,, Zhang et al. have reported that DAIZAC, a selective high-affinity 5-HT 3 receptor antagonist produces dose-dependent anxiolytic-like behavioral changes in mouse elevated plus-maze model.  In addition, several high-affinity 5-HT 3 antagonists are significantly found to exhibit antianxiety activities in preclinical models and may be used as novel candidates for the management of anxiety disorders.  Furthermore, clinical studies have revealed the anxiolytic-like effects of various 5-HT 3 receptor antagonists. A previous study has shown that ondansetron effectively reversed the fear potentiated startle in humans.  Tropisetron, another 5-HT 3 antagonist revealed dose-dependent efficacy in generalized anxiety disorder patients.  Moreover, Freeman et al. have shown that ondansetron treatment decreased anxiety in patients as measured by Hamilton Anxiety Rating Scale and Clinical Global Impressions of Severity scale.  This suggests that 5-HT 3 receptor antagonists may be helpful for treatment of anxiety disorders in humans. However, the efficacy of the existing 5-HT 3 receptor antagonists is questionable as few reports have demonstrated the effect of 5-HT 3 receptor antagonists is no more than that of placebo.  Therefore, captivating the recent knowledge from the previous research done and activities quoted for various substituted and nonsubstituted carboxamide moieties, the current study was undertaken to investigate the neuropsychological activity of a novel molecule, QCM-13 with 5-HT 3 receptor antagonistic activity for the management of anxiety-like deficits in validated behavioral rodent models of anxiety.
| Materials and Methods|| |
Experiments on animal were conducted in adherence to the approved protocol of the Institutional Animal Ethics Committee (IAEC) of Birla Institute of Technology and Science (BITS), Pilani, India (protocol no. IAEC/RES/04/01, dated 22.04.09). Swiss Albino mice (22-27 g) and Wistar rats (200-250 g) of either sex were purchased from Hisar Agricultural University, Haryana, India. Male and female animals were housed in separate cages and maintained of standard laboratory conditions with alternating light and dark cycle of 12 h each, temperature 23 ± 2° C and humidity conditions 62% ±5% RH in the housing for at least 1-week before the commencement of the experiments. The animals had free access to food (standard pellet chow feed) and filtered water ad libitum. The animals were used only once for each experiment.
QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) [Figure 1] was synthesized by Medicinal Chemistry Group, BITSPilani, Rajasthan. The chemistry and analytical parameters are given in [Table 1]. m-chlorophenyl piperazine (mCPP) was purchased from Lancaster Chemicals, (USA). Buspirone (BUS) was obtained from Astron Research Ltd., India as a generic gift sample. Diazepam (DIA) was purchased from the Medical Centre BITS-Pilani. The drugs were freshly prepared in distilled water and administered intraperitoneally (i.p.) in a constant volume of 10 mL/kg for mice and 1 mL/kg for rat. All the dose administrations and experimentation were carried out between 10:00 and 13:00 h.
Elevated plus maze test
The elevated plus maze (EPM) model was first devised by Lister and has been further suggested since then.  It consisted of a plus-shaped apparatus with two open (16 cm × 5 cm) and two enclosed arms (16 cm × 5 cm × 12 cm) each with an open roof, joined together with a central square platform and elevated 25 cm from the floor. The apparatus was indirectly illuminated with a ceiling-suspended lamp (60 W) placed at a height of 100 cm above the apparatus. Mice were given QCM-13 (2 and 4 mg/kg, i.p.) or DIA (2 mg/kg, i.p.) or vehicle and after 30 min, mice were individually subjected to the test. During the test, each mouse was placed at the central platform facing the open arm. The number of entries and the time spent in open arms were recorded for 5 min and reported as percentage values. After each test, the apparatus was sprayed with alcohol and wiped thoroughly to remove residual odor.
The method of Crawley and Goodwin was adopted with slight modifications.  The light-dark (LD) model consisted of a polypropylene chamber (44 cm × 21 cm × 21 cm) in which two-third of the light chamber was separated from one-third dark chamber by a 13 cm long block having 5 cm high openings. The light chamber of the apparatus was illuminated with a 60 W bulb. Mice were given QCM-13 (2 and 4 mg/kg, i.p.) or DIA (2 mg/kg, i.p.) or vehicle and after 30 min, mice were individually subjected to the test. During the test, each mouse was placed in light chamber facing toward the bulb. The animal was keenly observed for latency of the first entry into dark chamber when kept initially in light chamber, number of entries and time spent in the light chamber over a time period of 5 min. The apparatus was cleaned as mentioned above.
Hole board test
The hole board (HB) model was first described by Boissier and Simon.  It comprised of a square wooden box measuring 26 cm × 26 cm with equally spaced 16 holes in the floor 2.2 cm in diameter. Mice were given QCM-13 (2 and 4 mg/kg, i.p.) or DIA (2 mg/kg, i.p.) or vehicle and after 30 min, mice were individually subjected to the test. During the test, each mouse was placed at the center of the platform and following exploratory parameters namely, the number of nose-poking (head dipping through the holes), crossing (total distance travelled across the holes in the open arena/ambulation scores) and rearing (when the mice stands upright on its hind paws), were recorded for a 5 min period. The apparatus was cleaned after every trial.
Open field test
The test was conducted as described elsewhere with slight modifications.  The apparatus consisted of a circular 90-cm diameter arena with 75-cm high aluminum walls and floor equally divided into 10 cm squares. A 60 W light bulb was positioned 90 cm above the base of the arena, which was the only source of illumination in the testing room. Each rat was given QCM-13 (2 and 4 mg/kg, i.p.) or DIA (2 mg/kg, i.p.) or vehicle and after 30 min individually placed in the center of the open field apparatus. The following parameters were noted for 5 min. Ambulation scores (number of squares crossed) and number of rearing episodes (when the rat stands upright on its hind paws) were noted as horizontal and vertical activity, respectively. The apparatus was cleaned after each session.
Mice were treated individually with a single dose of vehicle (distilled water 10 ml/kg, i.p.) or BUS (10 mg/kg, i.p.), a 5-HT 1A receptor partial agonist and dopamine D 2 antagonist or mCPP (1 mg/kg, i.p.), a 5-HT 2A/2C receptor agonist, 15 min before the test drug administration.  Thirty minutes after the QCM-13 injection, the animals were subjected to assay in EPM. The exploratory behavior in terms of % entries and % time spent in open arms was calculated. The dose of standard drug and the treatment schedule derived from pilot studies earlier conducted.
All the results are expressed as mean ± standard error of the mean. The data from the single drug treatment studies were subjected to one-way ANOVA followed by post-hoc Dunnet's test. The behavioral scores from interaction studies were analyzed using one-way ANOVA followed by Bonferroni's multiple comparison test. All the comparisons were made against the control (vehicle treatment), or as otherwise specified.
| Results|| |
Elevated plus maze test
The behavioral parameters measured in terms of % time spent and % entries in open arms (when all the four paws are inside) in EPM showed significant (P < 0.05) activity of QCM-13. Statistically significant increase in % entries as well as the % time spent in open arms when compared with the control group [Figure 2] was observed. The standard drug DIA also expressed a significant increase in % entries as well as % time spent in open arm when compared with control group. No marked difference in the scores obtained from the tested and standard drug were observed.
|Figure 2: Effects of QCM-13 (2-4 mg/kg, intraperitoneally [i.p.]) and diazepam (2 mg/kg, i.p.) treatment in elevated plus maze study in mice. The columns represent the % entries in open arms (a) and % time spent in open arms (b). Error bars represent mean ± standard error of the mean. *P < 0.05 versus vehicle treatment, n = 6/group|
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Hole board assay
The exploratory parameters in HB test such as number of nose-poking, crossing and rearings were significantly increased with decreased fecal pellets by QCM-13 (2 and 4 mg/kg) as well as by DIA (2 mg/kg) as compared with control [Table 2].
QCM-13 at the tested doses responded well in the LD model for various behavioral indices, such as number of entries in light chamber, latency of first entry and time spent in light chamber. The drug exhibited an increased preference as well as time spent in light chamber. Similar behavior was observed with the standard drug (DIA, 2 mg/kg) as listed in [Table 3].
Open field test
The test drug QCM-13, at higher dose of 4 mg/kg showed significant (P < 0.05) activity in the open field (OF) test, with increased neurobehavioral parameters (number of crossings and rearings) when compared with control. However, the test drug at the dose of 2 mg/kg showed a significant number of rearings but an insignificant number of crossings. This might be due indifferent behavior shown by the animals. The standard drug DIA at 2 mg/kg also exhibited significant activity in the test [Figure 3].
|Figure 3: Effects of QCM-13 (2-4 mg/kg, intraperitoneally [i.p.]) and diazepam (2 mg/kg, i.p.) treatment in open field test in rats. The columns represent the ambulation scores (number of squares crossed) (a) and number of rearings (when rat stands on its hind paws) (b). Error bars represent mean ± standard error of the mean. *P < 0.05 versus control/ vehicle treatment, n = 6/ group|
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In the interaction study, the effect of mCPP (1 mg/kg, i.p.) and BUS (10 mg/kg, i.p.) was studied using EPM in QCM-13 pretreated animals to determine the probable activity of the test compound in the aforementioned animal model. mCPP decreased % entries and % time spent in open arms compared to control, also there was no significant alteration in the activity by QCM-13 [Figure 4]. In another interaction study with the BUS, the test drug at 4 mg/kg, but not at 2 mg/kg expressed a significant increase in % entries and % time spent in open arms [Figure 5].
|Figure 4: Effect of QCM-13 (2-4 mg/kg/intraperitoneally) pretreatment on anxiogenic effect of m-chlorophenyl piperazine (1 mg/kg) in mice elevated plus maze. The columns represent the % entries in open arms (a) and % time spent in open arms (b). Error bars represent mean ± standard error of the mean. *P < 0.05 versus vehicle treatment, n = 6/group|
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|Figure 5: Effect of QCM-13 (2-4 mg/kg/ intraperitoneally [i.p.]) pretreatment on anxiolytic activity of buspirone (BUS) (10 mg/kg, i.p.) in elevated plus maze study in mice. The columns represent the % entries in open arms (a) and % time spent in open arms (b). Error bars represent mean ± standard error of the mean. *P < 0.05 versus vehicle treatment, #P < 0.05 versus BUS treated group, n = 6/group|
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| Discussion|| |
Serotonergic system plays a vital role in both peripheral and central systems. Centrally, serotonin as a neurotransmitter distributed in the brain stem (e.g. nucleus tractus solitarius, area postrema, and spinal trigeminal nucleus) as well as the forebrain (covering hippocampus, amygdala, nucleus accumbens, putamen, and caudate) regulates emotional and behavioral conditions along with other neurotransmitters.  It plays a primary role in the control of anxious behavior of both humans and animals.
For psycho-pharmacological investigations, whole animal models have always been preferred and in particular, a series of animal (such as behavioral, mechanistic) models and interaction studies have made a pivotal contribution to explore the role of the serotonergic pathway in mood related disorders like depression and anxiety.  In our earlier study, QCM-13 (2 and 4 mg/kg, i.p.) was evaluated for antidepressant like activity.  In this study, neuropharmacological effects of QCM-13 at the tested dose levels (2 and 4 mg/kg) were examined on anxiety-like effects with the aim to develop novel ligands with versatile effects in mood disorders. QCM-13 was primarily analyzed for log P value and was found to be optimum to cross the blood brain barrier and to reach the target sites. Further, antagonistic potential at 5-HT 3 receptor was assessed as pA 2 value defined as, the negative logarithm to base 10 of the molar concentration of an antagonist that makes it necessary to double the concentration of the agonist needed to elicit the original submaximal response obtained in the absence of antagonist.  The pA 2 value of QCM-13 was found to be comparable with the standard ondansetron indicating the potential pharmacological activity at the molecular level. In-situ smooth muscle contraction studies using guinea pig ileum (data not shown) were performed to confirm the selective 5-HT 3 antagonistic potential of the same. In our earlier study, the drug showed significant synergistic activity in interaction studies with standard marketed drugs like (fluoxetine, bupropion) indicated that the pharmacological activity involved monoaminergic pathway with optimization of abnormalities in the serotonergic (substantially), dopaminergic and noradrenergic pathways.  While assessing the neuropsycological activity of a compound, an increase in baseline locomotion can lead to a false-positive result, therefore QCM-13 was evaluated and was found to exhibit insignificant locomotor effects as compared to control. , However, without affecting the locomotor scores, significant activity was observed in EPM, LD model, HB assay and OF test indicating alleviation of behavioral deficits in the animals, revealing the antianxiety-like activity of the tested compound. DIA (2 mg/kg) was taken as the standard drug for antianxiety models tested in the current study, which was effective in all the behavioral test performed indicating the validity of the anxiety/antianxiety models used.
EPM, LD, HB and OF tests have been widely used for the evaluation of anxiogenic and anxiolytic activity of various compounds. , EPM is one of the most widely used nonconditioned tests to evaluate anxiety-like behaviors and is widely applied for both rats and mice. , In this study, both QCM-13 (2 and 4 mg/kg) and DIA (2 mg/kg) increased the percentage open arm entries and percentage open arm time spent, reflecting the anxiolytic activity of the test compound similar to that of DIA. The increased percentage of open arm entries without altering the total arm entries (data not shown), suggested that QCM-13 possesses anxiolytic properties without increase in general locomotor activity.
LD model has wide acceptance for the screening of anxiety-like/antianxiety-like activity of test compounds. It involves the innate aversion of rodents to brightly illuminated field and the spontaneous exploratory behavior in response to mild stressors, that is, a new environment and light. Research has revealed that the percentage time spent in the light chamber is the most important indicator and a consistent parameter to assess the anxiolytic activity of a drug. , Though contrast opinions exist for the number of crossings to analyze the antianxiety activity, a large number of studies suggest that antianxiety drugs like DIA increase the number of crossings. , QCM-13 showed significant increase in latency as well as the time spent in the light chamber indicating the anxiolytic activity of the drug. Further, a decrease in the number of fecal pellets might further add on to the postulated activity of QCM-13.
In the HB assay, nose-poking and number of rearing indicate the exploratory behavior of mice. It is widely used to assess the anxiety and/or response to stress a novel environment.  QCM-13 and DIA significantly increased the number of nose-poking, crossings and rearings, in this sensitive model. These results indicated that QCM-13 similar to that of DIA has a satisfactory anxiolytic effect in this testing paradigm. Similarly, in OF test, the evaluation of the number of crossings, rearings, and fecal pellets as behavioral parameters were conducted as the measures of exploration of the animal when exposed to novel open environment. There were significant increase in the number of crossings, rearings and decrease in fecal pellets. The data corroborate the results of previous tested models and further confirm the anxiolytic role of QCM-13.
In the interaction study with mCPP, an anxiogenic compound, the test drug did not show any significant reduction in anxiogenic activity, which may reflect the drug does not have activity towards 5-HT 2 receptor. In an interaction with standard anxiolytic BUS, the test drug showed significant potentiation of antianxiety activity indicating the synergistic action of the compounds. This further indicated the probable mechanism of test drug involving directly or indirectly modulation of serotonin system. , Previous reports have shown that, 5-HT 3 receptor antagonists facilitate serotonergic neurotransmission, while several clinical evidences indicate the altered serotonergic functions associated with anxiety disorder patients. , It is proposed that the antagonism of 5-HT 3 receptor may increase the availability of serotonin at the other receptors sites (for example 5-HT 1A/1B ) which are directly involved in the regulation of mood and behavior.  Thus, it is likely that, QCM-13 may facilitate the serotonergic activity at other receptor sites (by blocking the specific 5-HT 3 receptors) and hence produces antianxiety-like effects.
Furthermore, it has been reported earlier that, being hetero-receptor, 5-HT 3 receptors regulate the release of other neurotransmitter such as gamma-aminobutyric acid (GABA), dopamine and nor-epinephrine in discrete areas of brain.  GABA is an inhibitory neurotransmitter, facilitatory action of which has been well-reported as the mechanism of anxiolytic action of benzodiazepines like DIA. , Therefore, modulatory effects of other neurotransmitters are required to be considered while demonstrating the overall mechanism of action of 5-HT 3 receptor antagonists like QCM-13. Further studies are require to be done to get the exact molecular basis of anxiolytic-like action of QCM-13 as observed in the present study, and it cannot be concluded based on the behavioral effects. However, the results of the current findings and literature evidence certainly give the plausible involvement of serotonergic modulation in the postulated effect of the tested compound.
| Conclusion|| |
Precisely, QCM-13 was evaluated for its neuropharmacological activity in various rodent models of anxiety. The validated animal models shed light on the potential effect of the drug. It was found that QCM-13 possesses antianxiety activity and may involve antagonism of 5-HT 3 receptors mediated modulation of serotonergic system as the possible mechanism. The present study certainly suggests that it may become a useful candidate for the management of anxiety-like disorders.
| Acknowledgments|| |
The authors are thankful to Birla Institute of Technology and Science (BITS), Pilani, India for providing support and research facilities to pursue this work.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]
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