Nature
April 24, 2016
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
PLoS ONE
June 14, 2016
Bryan L Roth, Simon Gibbons, Warunya Arunotayanun et al.
153 citations
Novel ketamine and phencyclidine analogues sold as designer drugs bind with high affinity to the same NMDA receptor site as the parent compounds, based on radioligand binding assays conducted through a national screening program. Methoxetamine and 3-MeO-PCE, along with the 3- and 4-methoxy analogues of phencyclidine, all showed strong affinity for the PCP-site on the glutamate NMDA receptor. Methoxetamine and phencyclidine and its analogues also bound appreciably to the serotonin transporter, while the PCP analogues had high affinity for sigma receptors. NMDA receptor antagonism likely explains their dissociative and psychotomimetic effects in humans; additional receptor actions may contribute to side effects.
Cell
May 11, 2023
Isha Singh, Anubha Seth, Christian B Billesbølle et al.
97 citations
Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.
Neuron
July 15, 2025
Manish K Jain, Ryan H Gumpper, Samuel T Slocum et al.
42 citations
Classical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.
Bioorganic & medicinal chemistry letters
June 1, 2013
Warunya Arunotayanun, Jeffrey W Dalley, Xi-Ping Huang et al.
41 citations
Two widely marketed novel psychoactive drugs, alpha-methyl-tryptamine and 5-methoxy-N,N-diallyl-tryptamine, were analyzed for their chemical structure and binding to serotonin receptor subtypes. These tryptamine-derived compounds, sold without restriction, can cause psychosis and hallucinations that may lead to injury or death. The study elucidates their structures and receptor binding profiles, providing insight into their pharmacological actions.
Cardiovascular toxicology
January 1, 2016
Kenneth Alper, Rong Bai, Nian Liu et al.
35 citations
Ibogaine, a compound used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. This study measured how strongly several iboga alkaloids block hERG channels in human cells. Ibogaine and its metabolite noribogaine blocked hERG channels with IC50 values around 2-4 µM, while 18-methoxycoronaridine (18-MC), a synthetic derivative, showed much weaker blockade (IC50 >50 µM). Although 18-MC bound to hERG channels with similar affinity as other compounds, it produced substantially less channel blockade. These findings suggest that 18-MC may have a safer cardiac profile than ibogaine, and that the structural differences among iboga alkaloids offer a useful model for studying hERG channel biology.
bioRxiv Preprint Server
June 13, 2022
Isha Singh, Anubha Seth, Christian B. Billesbølle et al.
8 citations
preprint
The serotonin transporter (SERT) adopts three conformations, and most antidepressants target its outward-open state. Ibogaine, which targets the inward-open state, has an unusual antidepressant profile but is cardiotoxic. Computational docking of over 200 million small molecules against the ibogaine-stabilized inward-open SERT identified 36 top compounds; 13 inhibited SERT with potencies from 29 to 5000 nM. Optimization yielded two inhibitors with Ki values as low as 3 nM that stabilized an outward-closed state and showed little off-target activity. A cryo-EM structure confirmed the predicted binding geometry. In mice, both compounds showed anxiolytic and antidepressant activity with potencies up to 200 times greater than fluoxetine.