Biochemical Pharmacology
April 13, 2020
A. Jensen, A. Halberstadt, Emil Märcher-Rørsted et al.
25 citations
Modifications to specific positions on the 25CN-NBOH molecule, a highly selective 5-HT2A receptor agonist, can retain or reduce its activity. Six new analogs were tested; 3′-methyl and fused-ring variants kept high 5-HT2A receptor activity, while 3′-methoxy and 3′-ethyl versions lost binding and potency. All six analogs showed only partial agonism or antagonism. In mice, 25CN-NBOH and a close analog triggered head-twitch responses (a hallmark of 5-HT2A activation) and reduced marble-burying behavior, suggesting potential benefits for cognitive rigidity disorders. A tritium-labeled version of 25CN-NBOH showed high binding affinity and selectivity for 5-HT2A receptors in rat brain tissue, providing a new tool for future receptor studies.
ACS chemical neuroscience
May 6, 2020
Emil Märcher-Rørsted, Adam L Halberstadt, Adam K Klein et al.
20 citations
The 2,5-dimethoxy motif found in many phenethylamine psychedelics has been considered essential for activating the serotonin 2A receptor (5-HT2AR). This study synthesized derivatives of 2C-B and DOB lacking either the 2- or 5-methoxy group and tested them in binding and functional assays at 5-HT2AR and 5-HT2CR, as well as in mice for head-twitch response, a behavioral proxy for psychedelic activity. Removing either methoxy group caused a modest drop in binding affinity and functional potency at both receptors, with larger effects from removing the 2-methoxy group. However, in mice, removal of either group drastically reduced head-twitch response. Thus, the 2,5-dimethoxy motif is important for in vivo potency, but this does not correlate with in vitro receptor affinity or potency.
Journal of Medicinal Chemistry
April 22, 2024
Karla Frydenvang, Emil Märcher-Rørsted, Anders A. Jensen et al.
7 citations
Classical psychedelics like psilocybin, LSD, and DMT show promise for treating depression, anxiety, and substance abuse, but their long-term therapeutic effects remain unclear. A new class of compounds, 2,5-dimethoxyphenylpiperidines, has been discovered as selective serotonin 2A receptor (5-HT2AR) agonists. Structure-activity studies identified LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with favorable drug-like properties, offering a potential tool to investigate the receptor's role in persistent therapeutic effects.
ACS Pharmacology & Translational Science
May 29, 2025
Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted et al.
3 citations
A new compound, LPH-5, acts as a potent partial agonist at the 5-HT2A receptor with high selectivity over related 5-HT2B and 5-HT2C receptors. In rats, LPH-5 induced head-twitch responses and produced both acute and persistent antidepressant-like effects. These findings suggest that selective activation of the 5-HT2A receptor alone can produce antidepressant effects, indicating that this receptor is a key component in the therapeutic action of classical psychedelics like psilocybin and LSD.
bioRxiv Preprint Server
April 19, 2024
Anders A. Jensen, Cláudia R. Cecchi, Meghan Hibicke et al.
preprint
A new compound called LPH-5 selectively activates the 5-HT2A receptor, unlike classical psychedelics which also affect related receptors. In rats, LPH-5 produced head-twitch responses (a behavioral marker of 5-HT2A activation) at doses of 0.5-1.0 mg/kg and showed antidepressant-like effects in three different rat models: Flinders Sensitive Line rats, adrenocorticotropic hormone-treated Sprague Dawley rats, and a Wistar Kyoto rat model designed to capture long-term antidepressant effects. The findings suggest that selective 5-HT2A receptor activation is sufficient for antidepressant potential, and that LPH-5 or similar selective compounds could represent a new generation of antidepressant drugs derived from psychedelics.