The Selective Serotonin 5‑HT_2A 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 eCollection Date: 2025-06-13 DOI:10.1021/acsptsci.5c00208

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

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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.

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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。

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

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