Nature
June 1, 2024
Audrey L Warren, David Lankri, Michael J Cunningham et al.
74 citations
Psychedelic substances like LSD and psilocybin show potential for treating neuropsychiatric disorders, primarily acting through the serotonin 5-HT2A receptor. However, 5-HT1A also contributes to the effects of tryptamine hallucinogens, especially 5-MeO-DMT from Colorado River toad toxin. Using cryo-EM structures, medicinal chemistry, and mouse behavior, researchers mapped how 5-MeO-DMT engages 5-HT1A. They characterized molecular determinants of signaling potency, efficacy, and selectivity at both 5-HT1A and 5-HT2A. A 5-HT1A-selective analogue of 5-MeO-DMT lacked hallucinogenic effects but retained anxiolytic-like and antidepressant-like activity in socially defeated animals, uncovering molecular aspects that may aid developing new neuropsychiatric medications.
ACS chemical biology
January 15, 2016
Madalee M Gassaway, Teresa L Jacques, Andrew C Kruegel et al.
23 citations
A novel iboga analog, XL-008, induces release of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells. It also potentiates GDNF release induced by fibroblast growth factor 2 (FGF2), increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture is mediated through the MEK and PI3K signaling pathways but not through PLCγ. This work describes a small-molecule approach to modulating growth factor signaling in the brain, relevant to treating neuropsychiatric disorders such as depression, anxiety, and addiction.
Nature communications
September 20, 2024
Václav Havel, Andrew C Kruegel, Benjamin Bechand et al.
18 citations
A new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga molecular structure to replace a key component with a benzofuran ring. These compounds lack the heart rhythm risks (proarrhythmic effects) of ibogaine and noribogaine when tested on human heart cells. In male rats, oxa-iboga compounds were more effective than ibogaine at reducing opioid use. They act as potent kappa opioid receptor agonists but produce different behavioral effects than typical kappa agonists. A single dose or short treatment with oxa-noribogaine led to long-lasting reductions in morphine, heroin, and fentanyl intake, reversed persistent opioid-induced pain sensitivity, and suppressed drug-seeking behavior in relapse models. These compounds offer a mechanistically distinct approach to treating opioid use disorder.
Neuropharmacology
May 1, 2025
Michael Noback, Johnny A Kenton, Adam K Klein et al.
2 citations
A compound called 2,5-dimethoxy-4-propylamphetamine (DOPR), a psychedelic that activates 5-HT2A receptors, can increase motivation in mice with low baseline motivation without causing hallucinogenic-like effects. In a progressive ratio breakpoint task (PRBT) involving 80 mice, doses as low as 0.0106 mg/kg improved performance only in animals with low initial motivation; high-performing mice were unaffected. The head-twitch response (HTR) assay in 72 mice showed hallucinogenic-like effects only at doses of 0.1 mg/kg or higher. These results suggest that low doses of DOPR might treat amotivated states while avoiding hallucinogenic side effects, warranting further research in rodents with disease-relevant conditions.