Abstract：
The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.
摘要：
化合物N-(3-(苯基硒基)丙-2-炔-1-基)苯甲酰胺(SePB),在有机结构中结合了硒原子和苯甲酰胺核，在小鼠中表现出快速的抗抑郁作用。这种作用受到5-羟色胺能系统的影响，代表了寻找治疗重度抑郁症（MDD）的新型抗抑郁药物的有希望的发展。通常会抵抗常规治疗。本研究旨在通过研究多巴胺能和去甲肾上腺素能系统在小鼠尾部悬浮试验（TST）中的参与并评估其药代动力学特征，进一步探索SePB抗抑郁样作用的机制。多巴胺能拮抗剂氟哌啶醇（0.05mg/kg，腹膜内（i.p.）），多巴胺（DA）受体的非选择性拮抗剂，SCH23390（0.01mg/kg，皮下（s.c.）），D1受体拮抗剂，和舒必利(50毫克/千克，i.p.),D2/3受体拮抗剂，在SePB（10mg/kg，胃内（i.g.））阻止了SePB在TST中的抗固定作用，证明这些受体参与SePB的抗抑郁样作用。去甲肾上腺素能拮抗剂哌唑嗪的给药（1mg/kg，i.p.),α1-肾上腺素能拮抗剂,育亨宾（1毫克/千克，i.p.),α2-肾上腺素能拮抗剂,和普萘洛尔（2mg/kg，i.p.),β-肾上腺素能拮抗剂,没有阻断SePB对TST的抗抑郁样作用，表明去甲肾上腺素能受体不参与这种作用。此外,SePB和安非他酮（去甲肾上腺素/多巴胺再摄取抑制剂）在超有效剂量（0.1和3mg/kg，分别)产生抗抑郁样作用。SePB还表现出良好的口服生物利用度和低毒性的计算吸收，分布，新陈代谢，排泄,和毒性（ADMET）分析。这些发现表明，SePB具有作为新的抗抑郁药候选药物的潜力，特别关注多巴胺能系统。
