The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents

Jensen, A. A.; Cecchi, C. R.; Hibicke, M.; Bach, A. H.; Kaadt, E.; Marcher-Rorsted, E.; Nichols, C. D.; Elfving, B.; Kristensen, J. L. L.

doi:10.1101/2024.04.19.590212

bioRxiv · 10.1101/2024.04.19.590212

The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents

Jensen, A. A.·Cecchi, C. R.·Hibicke, M.·Bach, A. H.·Kaadt, E.·Marcher-Rorsted, E.·Nichols, C. D.·Elfving, B.·Kristensen, J. L. L.

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Abstract

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-HT2A receptor (5-HT2AR) and to exhibit pronounced selectivity for this receptor over the related 5-HT2B and 5-HT2C 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-HT2AR 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-HT2AR 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-HT2AR- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.

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Jensen, A. A., Cecchi, C. R., Hibicke, M., Bach, A. H., Kaadt, E., Marcher-Rorsted, E., Nichols, C. D., Elfving, B., Kristensen, J. L. L.. 2024-04-22. The selective 5-HT2A receptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents. https://doi.org/10.1101/2024.04.19.590212

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