Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
J Psychopharmacol. 2022 Jul;36(7):819-835. doi: 10.1177/02698811221095528. Epub 2022 May 30.
Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology.
In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect.
The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies.
Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors.
This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems.
抑郁症是一种影响全球数百万人的疾病，发现和开发有效和安全的抗抑郁药物是精神药理学的重要课题之一。
本研究旨在研究具有 2,3-苯并二氮杂卓结构的抗焦虑药物托啡司坦的潜在抗抑郁样活性，并阐明介导这种作用的药理学机制。
通过悬尾和改良强迫游泳试验研究托啡司坦的抗抑郁样活性。通过药理学拮抗、分子对接和分子动力学模拟研究，阐明托啡司坦与 µ 和 δ 阿片受体亚型的可能相互作用。
托啡司坦（50 和 100mg/kg）显著缩短了悬尾和改良强迫游泳试验中小鼠的不动时间。该药物在相同剂量下延长了改良强迫游泳试验中测量的游泳和攀爬行为的持续时间。25mg/kg 剂量无效。机制研究表明，预先用对氯苯丙氨酸甲酯（5-羟色胺合成抑制剂；连续 4 天，100mg/kg）、α-甲基-para-酪氨酸甲酯（儿茶酚胺合成抑制剂；100mg/kg）、naloxonazine（选择性 µ 阿片受体阻滞剂，7mg/kg）和 naltrindole（选择性 δ 阿片受体阻滞剂，0.99mg/kg）预处理消除了托啡司坦 50mg/kg 剂量在悬尾试验中引起的抗不动作用。我们的计算机模拟研究支持了行为学发现，即托啡司坦的抗抑郁样作用是由 5-羟色胺能、儿茶酚胺能和阿片能系统介导的。
这项研究首次表明托啡司坦具有通过 5-羟色胺能、儿茶酚胺能和阿片能系统介导的抗抑郁样活性。
