Jensen Anders A, Cecchi Claudia R, Hibicke Meghan, Bach Astrid H, Kaadt Erik, Märcher-Rørsted Emil, Nichols Charles D, Elfving Betina, Kristensen Jesper L
Lophora ApS, 2920 Charlottenlund, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.
ACS Pharmacol Transl Sci. 2025 May 29;8(6):1791-1803. doi: 10.1021/acsptsci.5c00208. eCollection 2025 Jun 13.
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 [()-3-(2,5-dimethoxy-4-(trifluoromethyl)-phenyl)-piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT receptor (5-HTR) with pronounced selectivity for 5-HTR over the related 5-HTR and 5-HTR 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-HTR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.
迷幻剂已成为一种有前景的心理健康疾病治疗方法，目前在众多临床试验中正在探索裸盖菇素和麦角酸二乙酰胺（LSD）的治疗潜力。这促使人们寻找比传统的、作用较为广泛的经典迷幻剂具有更特异性药理活性的新型药物。在此，我们展示了一种此类化合物LPH-5 [()-3-(2,5-二甲氧基-4-(三氟甲基)-苯基)-哌啶] 的详细药理特性。在一系列功能试验中，发现LPH-5是5-羟色胺受体（5-HTR）的强效部分激动剂，对5-HTR的选择性明显高于相关的5-HTR和5-HTR。LPH-5在大鼠中剂量依赖性地诱发头部抽搐反应（HTR）以及强烈的急性和持续性抗抑郁样效应。这些结果表明，选择性5-HTR激活具有抗抑郁潜力，并表明该活性成分是经典迷幻剂治疗效果的关键。
