DSP-6745, a novel 5-hydroxytryptamine modulator with rapid antidepressant, anxiolytic, antipsychotic and procognitive effects.

IF 3.5 3区 医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-11-01 Epub Date: 2024-06-10 DOI:10.1007/s00213-024-06629-2
Maiko Kitaichi, Taro Kato, Hitomi Oki, Ayaka Tatara, Takuya Kawada, Kenji Miyazaki, Chihiro Ishikawa, Katsuyuki Kaneda, Isao Shimizu
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Abstract

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention.

Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms.

Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition.

Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.

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DSP-6745,一种新型的 5-羟色胺调节剂,具有快速抗抑郁、抗焦虑、抗精神病和促进认知的作用。
背景:目前重度抑郁症的治疗面临挑战,包括缓解率低、起效晚以及因精神病和认知功能障碍等合并症状导致的严重程度恶化。5-羟色胺(5-HT)神经递质与多种精神疾病有关,其作为药物靶点的潜力持续受到关注:本研究阐明了新型 5-HT 调节剂 DSP-6745 对抑郁症及其合并症状的影响:结果:体外放射性配体结合和功能测试显示,DSP-6745是5-羟色胺转运体和5-羟色胺2A、5-羟色胺2C和5-羟色胺7受体的强效抑制剂。在体内,DSP-6745(6.4 和 19.1 毫克/千克,游离碱,口服)不仅增加了内侧前额叶皮层中 5-羟色胺、去甲肾上腺素和多巴胺的释放,还增加了谷氨酸的释放。通过 SmartCube® 进行的体内小鼠表型筛选结果表明,DSP-6745 具有抗抑郁、抗焦虑和抗精神病类信号的行为特征。单次口服剂量的DSP-6745(6.4和19.1毫克/千克)在大鼠强迫游泳试验中显示出快速的抗抑郁样疗效,甚至在服药后24小时仍有疗效;在大鼠社会互动试验中显示出抗焦虑活性。此外,DSP-6745(12.7 毫克/千克,口服)还能改善阿朴吗啡诱导的大鼠前脉冲抑制缺陷。在用于评估注意力和行为抑制等认知功能的狨猴迂回物体检索任务中,DSP-6745(7.8 mg/kg,p.o.)增强了认知能力:这些数据表明,DSP-6745是一种多模式5-羟色胺受体拮抗剂和5-羟色胺转运体抑制剂,有可能成为一种快速起效的抗抑郁药,在减轻抑郁症的合并症状方面具有疗效。
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来源期刊
Psychopharmacology
Psychopharmacology 医学-精神病学
CiteScore
7.10
自引率
5.90%
发文量
257
审稿时长
2-4 weeks
期刊介绍: Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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