The Selective Serotonin 5‑HT<sub>2A</sub> Receptor Agonist (<i>S</i>)‑3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents.
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 [(<i>S</i>)-3-(2,5-dimethoxy-4-(trifluoromethyl)-phenyl)-piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT<sub>2A</sub> receptor (5-HT<sub>2A</sub>R) with pronounced selectivity for 5-HT<sub>2A</sub>R over the related 5-HT<sub>2B</sub>R and 5-HT<sub>2C</sub>R 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<sub>2A</sub>R activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.
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