The selective 5-HT <sub>2A</sub> receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents
Abstract
<h4>ABSTRACT</h4> Psychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the results of an elaborate preclinical 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 2A R) and to exhibit pronounced selectivity for this receptor over the related 5-HT 2B and 5-HT 2C receptors in a range of functional assays. LPH-5 (0.375 – 12.0 mg/kg, i.p. ) dose-dependently induced head-twitch responses (HTR) in Sprague Dawley rats, with substantial 5-HT 2A R engagement being observed at 0.5-1.0 mg/kg. Acute administration of LPH-5 (1.5 mg/kg, i.p .) induced robust antidepressant-like effects in Flinders Sensitive Line rats and adrenocorticotropic hormone-treated Sprague Dawley rats, and LPH-5 (0.3 and 1.5 mg/kg, i.p .) induced significant effects in a recently developed Wistar Kyoto rat model proposed to reflect the long-term antidepressant-like effects produced by psychedelics in humans. In conclusion, selective 5-HT 2A R activation, as mediated here by LPH- 5, seems to hold antidepressant potential, suggesting that this activity component is key for the beneficial effects of classical psychedelics. Hence, we propose that LPH-5 and other 5-HT 2A R- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.
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