The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents

IF 4.9 Q1 CHEMISTRY, MEDICINAL

ACS Pharmacology and Translational Science Pub Date : 2025-05-29 DOI:10.1021/acsptsci.5c0020810.1021/acsptsci.5c00208

Anders A. Jensen, Claudia R. Cecchi, Meghan Hibicke, Astrid H. Bach, Erik Kaadt, Emil Märcher-Rørsted, Charles D. Nichols, Betina Elfving and Jesper L. Kristensen*,

{"title":"The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents","authors":"Anders A. Jensen, Claudia R. Cecchi, Meghan Hibicke, Astrid H. Bach, Erik Kaadt, Emil Märcher-Rørsted, Charles D. Nichols, Betina Elfving and Jesper L. Kristensen*, ","doi":"10.1021/acsptsci.5c0020810.1021/acsptsci.5c00208","DOIUrl":null,"url":null,"abstract":"Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed pharmacological characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2A receptor (5-HT2AR) with pronounced selectivity for 5-HT2AR over the related 5-HT2BR and 5-HT2CR in a range of functional assays. LPH-5 dose-dependently induced head-twitch responses (HTR) as well as robust acute and persistent antidepressant-like effects in rats. These results suggest that selective 5-HT2AR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1791–1803 1791–1803"},"PeriodicalIF":4.9000,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Pharmacology and Translational Science","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsptsci.5c00208","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed pharmacological characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT_2A receptor (5-HT_2AR) with pronounced selectivity for 5-HT_2AR over the related 5-HT_2BR and 5-HT_2CR in a range of functional assays. LPH-5 dose-dependently induced head-twitch responses (HTR) as well as robust acute and persistent antidepressant-like effects in rats. These results suggest that selective 5-HT_2AR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.

查看原文本刊更多论文

选择性5-羟色胺5-HT2A受体激动剂(S)-3-（2,5-二甲氧基-4-（三氟甲基）苯基）哌啶（LPH-5）在啮齿动物中诱导持久和强大的抗抑郁样作用

致幻剂已经成为一种很有前景的精神疾病治疗方法，裸盖菇素和麦角酸二乙胺（LSD）的治疗潜力目前正在许多临床试验中进行。这促使人们寻找具有比混杂的经典致幻剂更具体药理活性的新型药剂。在这里，我们介绍了一种这样的化合物LPH-5 [(S)-3-（2,5-二甲氧基-4-（三氟甲基）苯基）哌啶]的详细药理学表征。在一系列功能试验中，LPH-5被发现是5-HT2A受体（5-HT2AR）的有效部分激动剂，对5-HT2AR的选择性明显高于相关的5-HT2BR和5-HT2CR。LPH-5剂量依赖性诱导大鼠头抽搐反应（HTR）以及强大的急性和持续性抗抑郁样作用。这些结果表明，选择性5-HT2AR激活具有抗抑郁潜力，并表明该活性成分是经典迷幻药治疗效果的关键。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.