Original Article
Pharmacological evaluation of novel 5‑HT3 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, ABSTRACT Birla Institute of Objective: In the last few decades, serotonin type‑3 (5‑HT ) receptor antagonists have been identified as potential Technology and Science, 3 targets for anxiety disorders. In preclinical studies, 5‑HT antagonists have shown promising antianxiety effects. Pilani, Rajasthan, India 3 In this study, a novel 5‑HT3 receptor antagonist, QCM‑13(N‑cyclohexyl‑3‑methoxyquinoxalin‑2‑carboxamide) Address for correspondence: was evaluated for anxiolytic‑like activity in rodent behavioral test battery. Materials and Methods: Mice were Ms. Deepali Gupta, given QCM‑13 (2 and 4 mg/kg, intraperitoneally [i.p.]) or diazepam (2 mg/kg, i.p.) or vehicle and after 30 min, E‑mail: deepaligupta2010@ mice were subjected to four validated behavioral test batteries viz. elevated plus maze, hole board, light‑dark gmail.com and open field tests. Interaction study of QCM‑13 with m‑chlorophenyl piperazine (mCPP) (mCPP, a 5‑HT2A/2C
receptor agonist, 1 mg/kg, i.p.) and buspirone (BUS, a partial 5‑HT1A 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‑HT3 receptor antagonist with standard anxiolytics may improve therapeutic efficacy.
Received : 04‑09‑13 Review completed : 14‑12‑13
Accepted : 17‑05‑14 KEY WORDS: 5‑HT3 receptor antagonist, antianxiety activity, QCM‑13
erotonin is a biogenic amine biochemically derived such as anxiety, depression and other comorbid disorders causing S from the tryptophan, plays an important role as a significant personal distress, reduced “quality of life,” increased neurotransmitter in the monoaminergic pathways. Originating morbidity and mortality as well as a significant economic burden from raphe nuclei, it provides an intense and widespread on an individual.[4] innervation of corticolimbic structures such as frontal cortex, septum, amygdala and hippocampus, the central areas for Apart from serotonin reuptake inhibitors, serotonin transporters controlling mood and emotional behavior.[1‑3] Thus, disturbances and neurotransmission modulators, extensive research have proven in the activity of serotonergic system may lead to mood disorders the involvement of serotonin receptors agonists/antagonists (at the molecular level, including more or less all types of 5‑HT Access this article online receptors and their sub‑types) acting on both pre (5‑HT1B) as
Quick Response Code: well as postsynaptic (5‑HT1, 5‑HT2, 5‑HT4, 5‑HT5‑7) receptors in Website: one or another form of anxiety disorder. Thus, the contribution www.jpbsonline.org of serotonin type‑3 receptor and sub‑types in the management of psychological disorders is quite significant.[3] DOI:
10.4103/0975-7406.154429 The pharmacological activity of various drugs with 5‑HT3 receptor antagonistic activity has also been evaluated for
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.
Journal of Pharmacy and Bioallied Sciences April-June 2015 Vol 7 Issue 2 103 Gupta, et al.: QCM-13 as antianxiety agent generalized anxiety disorders or comorbid anxieties, which Drugs are being commercially available for nonpsychological disorders such as antiemetics, prokinetics.[3] In example, QCM‑13 (N‑cyclohexyl‑3‑methoxyquinoxalin‑2‑carboxamide) ondansetron, a 5‑HT3 receptor antagonist, is studied for the [Figure 1] was synthesized by Medicinal Chemistry Group, management of depression and anxiety.[5,6] Though some BITSPilani, Rajasthan. The chemistry and analytical parameters contradictory results are observed for its anxiolytic activity it are given in Table 1. m‑chlorophenyl piperazine (mCPP) was has been found effective both in humans as well as in rodents. purchased from Lancaster Chemicals, (USA). Buspirone (BUS) [7‑9] was obtained from Astron Research Ltd., India as a generic gift Other 5‑HT3 antagonists such as tropisetron, granisetron, ricasetron, and zacopride have also been reported as potent sample. Diazepam (DIA) was purchased from the Medical Centre anxiolytic agents.[9‑12] Zhang et al. have reported that BITS‑Pilani. The drugs were freshly prepared in distilled water and administered intraperitoneally (i.p.) in a constant volume of DAIZAC, a selective high‑affinity 5‑HT3 receptor antagonist produces dose‑dependent anxiolytic‑like behavioral changes 10 mL/kg for mice and 1 mL/kg for rat. All the dose administrations in mouse elevated plus‑maze model.[13] In addition, several and experimentation were carried out between 10:00 and 13:00 h. high‑affinity 5‑HT3 antagonists are significantly found to exhibit antianxiety activities in preclinical models and Elevated plus maze test may be used as novel candidates for the management of anxiety disorders.[14] Furthermore, clinical studies have The elevated plus maze (EPM) model was first devised by Lister [18] revealed the anxiolytic‑like effects of various 5‑HT receptor and has been further suggested since then. It consisted of 3 a plus‑shaped apparatus with two open (16 cm × 5 cm) and antagonists. A previous study has shown that ondansetron two enclosed arms (16 cm × 5 cm × 12 cm) each with an effectively reversed the fear potentiated startle in humans. open roof, joined together with a central square platform and [15] Tropisetron, another 5‑HT antagonist revealed 3 elevated 25 cm from the floor. The apparatus was indirectly dose‑dependent efficacy in generalized anxiety disorder [16] illuminated with a ceiling‑suspended lamp (60 W) placed patients. Moreover, Freeman et al. have shown that at a height of 100 cm above the apparatus. Mice were given ondansetron treatment decreased anxiety in patients as QCM‑13 (2 and 4 mg/kg, i.p.) or DIA (2 mg/kg, i.p.) or vehicle measured by Hamilton Anxiety Rating Scale and Clinical and after 30 min, mice were individually subjected to the test. [17] Global Impressions of Severity scale. This suggests that During the test, each mouse was placed at the central platform 5‑HT3 receptor antagonists may be helpful for treatment facing the open arm. The number of entries and the time spent of anxiety disorders in humans. However, the efficacy of in open arms were recorded for 5 min and reported as percentage the existing 5‑HT3 receptor antagonists is questionable as values. After each test, the apparatus was sprayed with alcohol few reports have demonstrated the effect of 5‑HT3 receptor and wiped thoroughly to remove residual odor. antagonists is no more than that of placebo.[14] Therefore, captivating the recent knowledge from the previous research Light‑dark model done and activities quoted for various substituted and nonsubstituted carboxamide moieties, the current study was The method of Crawley and Goodwin was adopted with slight undertaken to investigate the neuropsychological activity of modifications.[19] The light‑dark (LD) model consisted of a a novel molecule, QCM‑13 with 5‑HT3 receptor antagonistic activity for the management of anxiety‑like deficits in validated behavioral rodent models of anxiety.
Materials and Methods
Animals
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 Figure 1: The structure of QCM-13 rats (200-250 g) of either sex were purchased from Hisar Agricultural University, Haryana, India. Male and female animals Table 1: Chemistry and analytical parameters of QCM‑13 were housed in separate cages and maintained of standard Parameters Values laboratory conditions with alternating light and dark cycle of IUAC name N‑cyclohexyl‑3‑methoxyquinoxalin‑2‑carboxamide 12 h each, temperature 23 ± 2° C and humidity conditions pA2 value 7.6 62% ±5% RH in the housing for at least 1‑week before the log P value 2.91 commencement of the experiments. The animals had free access Melting point 148-150°C to food (standard pellet chow feed) and filtered water ad libitum. QCM‑13: N‑cyclohexyl‑3‑methoxyquinoxalin‑2‑carboxamide, The animals were used only once for each experiment. IUAC: International union of pure and applied chemistry
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polypropylene chamber (44 cm × 21 cm × 21 cm) in which Statistical analysis two‑third of the light chamber was separated from one‑third dark chamber by a 13 cm long block having 5 cm high openings. All the results are expressed as mean ± standard error of the The light chamber of the apparatus was illuminated with a mean. The data from the single drug treatment studies were 60 W bulb. Mice were given QCM‑13 (2 and 4 mg/kg, i.p.) subjected to one‑way ANOVA followed by post‑hoc Dunnet’s or DIA (2 mg/kg, i.p.) or vehicle and after 30 min, mice were test. The behavioral scores from interaction studies were individually subjected to the test. During the test, each mouse analyzed using one‑way ANOVA followed by Bonferroni’s was placed in light chamber facing toward the bulb. The animal multiple comparison test. All the comparisons were made was keenly observed for latency of the first entry into dark against the control (vehicle treatment), or as otherwise chamber when kept initially in light chamber, number of entries specified. and time spent in the light chamber over a time period of 5 min. The apparatus was cleaned as mentioned above. Results
Hole board test Elevated plus maze test
The hole board (HB) model was first described by Boissier The behavioral parameters measured in terms of % time spent and Simon.[20] It comprised of a square wooden box measuring and % entries in open arms (when all the four paws are inside) 26 cm × 26 cm with equally spaced 16 holes in the floor 2.2 cm in EPM showed significant (P < 0.05) activity of QCM‑13. in diameter. Mice were given QCM‑13 (2 and 4 mg/kg, i.p.) Statistically significant increase in % entries as well as the % or DIA (2 mg/kg, i.p.) or vehicle and after 30 min, mice were time spent in open arms when compared with the control individually subjected to the test. During the test, each mouse group [Figure 2] was observed. The standard drug DIA also expressed a significant increase in % entries as well as % time was placed at the center of the platform and following exploratory spent in open arm when compared with control group. No parameters namely, the number of nose‑poking (head dipping marked difference in the scores obtained from the tested and through the holes), crossing (total distance travelled across the standard drug were observed. holes in the open arena/ambulation scores) and rearing (when the mice stands upright on its hind paws), were recorded for a Hole board assay 5 min period. The apparatus was cleaned after every trial. The exploratory parameters in HB test such as number of Open field test nose‑poking, crossing and rearings were significantly increased with decreased fecal pellets by QCM‑13 (2 and 4 mg/kg) as The test was conducted as described elsewhere with slight well as by DIA (2 mg/kg) as compared with control [Table 2]. modifications.[21] 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 HQWU\LQRHQDUPV field apparatus. The following parameters were noted for 5 min. WLPHVSHQWLQRSHQDUPV 4&0 PJNJLS ',$ 4&0 PJNJLS ',$ Ambulation scores (number of squares crossed) and number of a b rearing episodes (when the rat stands upright on its hind paws) Figure 2: Effects of QCM-13 (2-4 mg/kg, intraperitoneally [i.p.]) and were noted as horizontal and vertical activity, respectively. The diazepam (2 mg/kg, i.p.) treatment in elevated plus maze study in mice. apparatus was cleaned after each session. 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 Interaction studies Table 2: Antianxiety‑like activity of QCM‑13 in hole board Mice were treated individually with a single dose of test in mice vehicle (distilled water 10 ml/kg, i.p.) or BUS (10 mg/kg, i.p.), Treatments Behavioral parameters a 5‑HT receptor partial agonist and dopamine D antagonist 1A 2 Nose‑pokings Crossings Rearings or mCPP (1 mg/kg, i.p.), a 5‑HT2A/2C receptor agonist, 15 min before the test drug administration.[22] Thirty minutes after Control 21.00±2.22 27.12±3.02 5.00±1.1 QCM‑13 (2 mg/kg) 34.00±0.83* 36.00±3.40* 6.24±1.56 the QCM‑13 injection, the animals were subjected to assay in QCM‑13 (4 mg/kg) 42.00±1.97* 41.37±1.91* 8.33±0.99* EPM. The exploratory behavior in terms of % entries and % DIA (2 mg/kg) 51.22±1.32* 46.00±2.83* 9.00±0.83* time spent in open arms was calculated. The dose of standard The values represent mean±SEM. *P<0.05 versus vehicle treatment drug and the treatment schedule derived from pilot studies n=6/group. SEM: Standard error of the mean, DIA: Diazepam, earlier conducted. QCM: N‑cyclohexyl‑3‑methoxyquinoxalin‑2‑carboxamide
Journal of Pharmacy and Bioallied Sciences April-June 2015 Vol 7 Issue 2 105 Gupta, et al.: QCM-13 as antianxiety agent
Light‑dark model behavioral conditions along with other neurotransmitters.[3] It plays a primary role in the control of anxious behavior of both QCM‑13 at the tested doses responded well in the LD model humans and animals. for various behavioral indices, such as number of entries in light chamber, latency of first entry and time spent in light chamber. For psycho‑pharmacological investigations, whole animal The drug exhibited an increased preference as well as time models have always been preferred and in particular, a series of spent in light chamber. Similar behavior was observed with the animal (such as behavioral, mechanistic) models and interaction standard drug (DIA, 2 mg/kg) as listed in Table 3. studies have made a pivotal contribution to explore the role of the serotonergic pathway in mood related disorders like depression Open field test and anxiety.[23] In our earlier study, QCM‑13 (2 and 4 mg/kg, i.p.) was evaluated for antidepressant like activity.[24] In this study, The test drug QCM‑13, at higher dose of 4 mg/kg showed neuropharmacological effects of QCM‑13 at the tested dose significant (P < 0.05) activity in the open field (OF) test, with levels (2 and 4 mg/kg) were examined on anxiety‑like effects with increased neurobehavioral parameters (number of crossings the aim to develop novel ligands with versatile effects in mood and rearings) when compared with control. However, the test disorders. QCM‑13 was primarily analyzed for log P value and was 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]. 1RRIUHDULQJ V Interaction studies DPEXODWLRQVFRUH V 4&0 PJNJLS ',$ 4&0 PJNJLS ',$ In the interaction study, the effect of mCPP (1 mg/kg, i.p.) a b and BUS (10 mg/kg, i.p.) was studied using EPM in QCM‑13 Figure 3: Effects of QCM-13 (2-4 mg/kg, intraperitoneally [i.p.]) and pretreated animals to determine the probable activity of the diazepam (2 mg/kg, i.p.) treatment in open field test in rats. The columns test compound in the aforementioned animal model. mCPP represent the ambulation scores (number of squares crossed) (a) and decreased % entries and % time spent in open arms compared number of rearings (when rat stands on its hind paws) (b). Error bars to control, also there was no significant alteration in the activity represent mean ± standard error of the mean. *P < 0.05 versus control/ vehicle treatment, n = 6/ group 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 4&0 4&0P&33 4&0 4&0P&33 arms [Figure 5]. Discussion
Serotonergic system plays a vital role in both peripheral and HQWULHVLQRSHQDUPV
WLPHVSHQWLQRSHQDUPV central systems. Centrally, serotonin as a neurotransmitter 4&0 GRVHPJNJLS 4&0 PJNJLS distributed in the brain stem (e.g. nucleus tractus solitarius, a b area postrema, and spinal trigeminal nucleus) as well as Figure 4: Effect of QCM-13 (2-4 mg/kg/intraperitoneally) pretreatment on the forebrain (covering hippocampus, amygdala, nucleus anxiogenic effect of m-chlorophenyl piperazine (1 mg/kg) in mice elevated accumbens, putamen, and caudate) regulates emotional and 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 Table 3: Antianxiety‑like activity of QCM‑13 in LD model in mice 4&0 4&0%86 Treatment Behavioral parameters 4&0 4&0%86 Onset Crossings Light Fecal pellets
(seconds) chamber %
time spent Control 35.00±12.34 13.00±4.00 22.94±1.70 3.14±3.60 HQWU\LQRSHQDUPV QCM‑13 21.16±3.56* 17.17±5.67* 33.39±1.09* 3.33±7.90 (2 mg/kg) 7LPHVSHQWLQRSHQDUPV 4&0 PJNJLS QCM‑13 27.83±6.77* 20.50±5.14* 46.30±6.71* 1.00±8.40* a 4&0 PJNJLS b (4 mg/kg) Figure 5: Effect of QCM-13 (2-4 mg/kg/ intraperitoneally [i.p.]) DIA 34.12±9.10 21.36±8.90* 58.47±5.60* 1.11±5.60* pretreatment on anxiolytic activity of buspirone (BUS) (10 mg/kg, i.p.) (2 mg/kg) in elevated plus maze study in mice. The columns represent the % The values shows mean±SEM. *P<0.05 versus vehicle treatment. entries in open arms (a) and % time spent in open arms (b). Error bars n=6/group. QCM: N‑cyclohexyl‑3‑methoxyquinoxalin‑2‑carboxamide, represent mean ± standard error of the mean. *P < 0.05 versus vehicle DIA: Diazepam, LD: Light‑dark, SEM: Standard error of the mean treatment, #P < 0.05 versus BUS treated group, n = 6/group
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found to be optimum to cross the blood brain barrier and to reach In the HB assay, nose‑poking and number of rearing indicate the
the target sites. Further, antagonistic potential at 5‑HT3 receptor exploratory behavior of mice. It is widely used to assess the anxiety [32] was assessed as pA2 value defined as, the negative logarithm to and/or response to stress a novel environment. QCM‑13 base 10 of the molar concentration of an antagonist that makes and DIA significantly increased the number of nose‑poking, it necessary to double the concentration of the agonist needed crossings and rearings, in this sensitive model. These results to elicit the original submaximal response obtained in the indicated that QCM‑13 similar to that of DIA has a satisfactory [25] absence of antagonist. The pA2 value of QCM‑13 was found anxiolytic effect in this testing paradigm. Similarly, in OF test, to be comparable with the standard ondansetron indicating the evaluation of the number of crossings, rearings, and fecal the potential pharmacological activity at the molecular level. pellets as behavioral parameters were conducted as the measures In‑situ smooth muscle contraction studies using guinea pig of exploration of the animal when exposed to novel open ileum (data not shown) were performed to confirm the selective environment. There were significant increase in the number
5‑HT3 antagonistic potential of the same. In our earlier study, of crossings, rearings and decrease in fecal pellets. The data the drug showed significant synergistic activity in interaction corroborate the results of previous tested models and further studies with standard marketed drugs like (fluoxetine, confirm the anxiolytic role of QCM‑13. bupropion) indicated that the pharmacological activity involved monoaminergic pathway with optimization of abnormalities in In the interaction study with mCPP, an anxiogenic compound, the serotonergic (substantially), dopaminergic and noradrenergic the test drug did not show any significant reduction in [24] pathways. While assessing the neuropsycological activity of anxiogenic activity, which may reflect the drug does not have a compound, an increase in baseline locomotion can lead to a activity towards 5‑HT2 receptor. In an interaction with standard false‑positive result, therefore QCM‑13 was evaluated and was anxiolytic BUS, the test drug showed significant potentiation found to exhibit insignificant locomotor effects as compared to of antianxiety activity indicating the synergistic action of the [25,26] control. However, without affecting the locomotor scores, compounds. This further indicated the probable mechanism significant activity was observed in EPM, LD model, HB assay of test drug involving directly or indirectly modulation of and OF test indicating alleviation of behavioral deficits in the [3,33] serotonin system. Previous reports have shown that, 5‑HT3 animals, revealing the antianxiety‑like activity of the tested receptor antagonists facilitate serotonergic neurotransmission, compound. DIA (2 mg/kg) was taken as the standard drug while several clinical evidences indicate the altered serotonergic for antianxiety models tested in the current study, which was functions associated with anxiety disorder patients.[3,14] It is effective in all the behavioral test performed indicating the proposed that the antagonism of 5‑HT receptor may increase validity of the anxiety/antianxiety models used. 3 the availability of serotonin at the other receptors sites (for example 5‑HT ) which are directly involved in the regulation EPM, LD, HB and OF tests have been widely used for the 1A/1B of mood and behavior.[3] Thus, it is likely that, QCM‑13 may evaluation of anxiogenic and anxiolytic activity of various facilitate the serotonergic activity at other receptor sites (by compounds.[7,27] EPM is one of the most widely used blocking the specific 5‑HT receptors) and hence produces nonconditioned tests to evaluate anxiety‑like behaviors and is 3 antianxiety‑like effects. widely applied for both rats and mice.[28,29] In this study, both QCM‑13 (2 and 4 mg/kg) and DIA (2 mg/kg) increased the Furthermore, it has been reported earlier that, being percentage open arm entries and percentage open arm time hetero‑receptor, 5‑HT receptors regulate the release of other spent, reflecting the anxiolytic activity of the test compound 3 neurotransmitter such as gamma‑aminobutyric acid (GABA), similar to that of DIA. The increased percentage of open arm dopamine and nor‑epinephrine in discrete areas of brain.[3] entries without altering the total arm entries (data not shown), suggested that QCM‑13 possesses anxiolytic properties without GABA is an inhibitory neurotransmitter, facilitatory action of increase in general locomotor activity. which has been well‑reported as the mechanism of anxiolytic action of benzodiazepines like DIA.[19,31] Therefore, modulatory LD model has wide acceptance for the screening of effects of other neurotransmitters are required to be considered while demonstrating the overall mechanism of action of 5‑HT anxiety‑like/antianxiety‑like activity of test compounds. It 3 involves the innate aversion of rodents to brightly illuminated receptor antagonists like QCM‑13. Further studies are require to field and the spontaneous exploratory behavior in response to be done to get the exact molecular basis of anxiolytic‑like action mild stressors, that is, a new environment and light. Research of QCM‑13 as observed in the present study, and it cannot be has revealed that the percentage time spent in the light concluded based on the behavioral effects. However, the results chamber is the most important indicator and a consistent of the current findings and literature evidence certainly give parameter to assess the anxiolytic activity of a drug.[2,30] the plausible involvement of serotonergic modulation in the Though contrast opinions exist for the number of crossings postulated effect of the tested compound. to analyze the antianxiety activity, a large number of studies suggest that antianxiety drugs like DIA increase the number of Conclusion crossings.[27,31] QCM‑13 showed significant increase in latency as well as the time spent in the light chamber indicating the Precisely, QCM‑13 was evaluated for its neuropharmacological anxiolytic activity of the drug. Further, a decrease in the activity in various rodent models of anxiety. The validated number of fecal pellets might further add on to the postulated animal models shed light on the potential effect of the drug. It activity of QCM‑13. was found that QCM‑13 possesses antianxiety activity and may
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