Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
KVSR Siddhartha College of Pharmaceutical Sciences, Vijaywada, Andhra Pradesh 520001, India.
Eur J Pharmacol. 2014 Jul 15;735:59-67. doi: 10.1016/j.ejphar.2014.04.008. Epub 2014 Apr 18.
Depression and anxiety are the most debilitating mood disorders with poor therapeutic recovery rates. In the last decades, 5-HT3 receptor antagonists have been identified as potential agents for mood disorders. The current investigation focuses on evaluating the, antidepressant and anti-anxiety like effects of a novel 5-HT3 antagonist, 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide). Preliminary, in vitro 5-HT3 receptor binding affinity was performed in isolated longitudinal muscle-myenteric plexus from the guinea pig ileum. Consequently, neurobehavioral effects of 4i in acute and chronic rodent models were evaluated. In addition, involvement of serotonergic system in the postulated effects of the compound was analyzed by in vivo assay. in vitro, 4i demonstrated high 5-HT3 receptor antagonistic activity (pA2, 7.6). in vivo acute study, 4i exhibited decreased duration of immobility in forced swim and tail suspension tests, and increased exploratory parameters as number and duration of nose-poking in hole board test and latency and time spent in aversive brightly illuminated light chamber in light-dark model. Moreover, in chronic model of depression, i.e., olfactory bulbectomy with behavioral deficits, 4i reversed depressive anhedonia in sucrose preference test and anxious hyperactive behavior in open field test in rats. Furthermore, synergistic effect of 4i with fluoxetine (a selective serotonin reuptake inhibitor) and inhibitory effect of 1-(m-chlorophenyl)-biguanide (a 5-HT3 receptor agonist) revealed serotonergic modulation by 4i mediated 5-HT3 receptor antagonism, which was further confirmed by potentiation of 5-hydroxytryptophan (a serotonin synthesis precursor) induced head twitch response. These findings suggest the potential antidepressant and anti-anxiety like effects of 4i, which may be related to the modulation of serotonergic system.
抑郁和焦虑是最具破坏性的情绪障碍，治疗恢复率低。在过去的几十年中，5-HT3 受体拮抗剂已被确定为治疗情绪障碍的潜在药物。本研究重点评估新型 5-HT3 拮抗剂 4i（N-（3-氯-2-甲基苯基）喹喔啉-2-甲酰胺）的抗抑郁和抗焦虑样作用。初步在豚鼠回肠的分离纵向肌肉-肌间神经丛中进行了体外 5-HT3 受体结合亲和力实验。随后，评估了 4i 在急性和慢性啮齿动物模型中的神经行为效应。此外，通过体内试验分析了 5-羟色胺能系统在化合物假定作用中的参与。在体外，4i 表现出高 5-HT3 受体拮抗活性（pA2，7.6）。在体内急性研究中，4i 可减少强迫游泳和悬尾试验中的不动时间，并增加洞板试验中鼻戳的次数和持续时间、潜伏期和厌恶明亮光照室中的停留时间，以及在明亮-黑暗模型中探索性参数。此外，在嗅觉球切除术伴有行为缺陷的慢性抑郁模型中，4i 逆转了蔗糖偏好试验中的抑郁快感缺失和旷场试验中的焦虑多动行为。此外，4i 与氟西汀（一种选择性 5-羟色胺再摄取抑制剂）的协同作用和 1-（间氯苯基）-双胍（一种 5-HT3 受体激动剂）的抑制作用表明 4i 通过 5-HT3 受体拮抗作用介导 5-羟色胺能调制，这进一步通过增强 5-羟色氨酸（5-HT 合成前体）诱导的头部抽搐反应得到证实。这些发现表明 4i 具有潜在的抗抑郁和抗焦虑样作用，这可能与 5-羟色胺能系统的调节有关。
