Morphing of Ibogaine: A Successful Attempt into the Search for Sigma-2 Receptor Ligands.
Giuseppe Floresta, Maria Dichiara, Davide Gentile, Orazio Prezzavento, Agostino Marrazzo, Antonio Rescifina, Emanuele Amata
International Journal of Molecular Sciences January 23, 2019 DOI: 10.3390/ijms20030488 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Computational and experimental study Peer reviewed |
|---|---|
| Topics | Ibogaine |
| Keywords | Incazane Pinoline Tmem97 Molecular docking Scaffold-hopping Sigma-2 receptor research Neurological disease therapeutics Computational drug design |
| Citations | 16 |
| Key findings | Pinoline exhibited predicted high micromolar affinity and good selectivity for the sigma-2 receptor in a radioligand binding assay. |
Abstract
Ibogaine is a psychoactive indole alkaloid with high affinity for several targets including the σ₂ receptor. Indeed, extensive data support the involvement of the σ₂ receptor in neurological disorders, including Alzheimer's disease, schizophrenia, alcohol abuse and pain. Due to its serious side effects which prevent ibogaine from potential clinical applications, novel ibogaine derivatives endowed with improved σ₂ receptor affinity may be particularly beneficial. With the purpose to facilitate the investigation of iboga alkaloid derivatives which may serve as templates for the design of selective σ₂ receptor ligands, here we report a deconstruction study on the ibogaine tricyclic moiety and a successive scaffold-hopping of the indole counterpart. A 3D-QSAR model has been applied to predict the σ₂ pKi values of the new compounds, whereas a molecular docking study conducted upon the σ₂ receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for σ₂ receptor affinity through radioligand binding assay and the results confirmed the predicted high µM range of affinity and good selectivity. The obtained results could be helpful in the drug design process of new ibogaine simplified analogs with improved σ₂ receptor binding capabilities.
Comparable studies
Other experimental studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. In vitro (SERT) | 2007 | Laboratory study | |
| Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. | 1992 | Laboratory study | |
| The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. | 2012 | Experimental study | |
| Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. | 1995 | Experimental study | |
| Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. | 1995 | Laboratory study |
Citations in the library
Cited by 4
- The potential of psychedelics for the treatment of Alzheimer's disease and related dementias. European Neuropsychopharmacology November 1, 2023
- A narrative review of the pharmacological, cultural and psychological literature on ibogaine Journal of Psychedelic Studies 2021
- Increased cortical thickness and decreased brain age among special operations veterans with blast TBI after a magnesium-ibogaine protocol iScience February 21, 2026
- Ibogaine for the treatment of Parkinson's disease: A case report Journal of Psychedelic Studies January 6, 2026
Cites 8
- Ibogaine possesses a selective affinity for sigma 2 receptors. Life Sciences 1995
- Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Research February 7, 1992
- Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity. Psychopharmacology April 1, 1995
- Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review. Human & Experimental Toxicology March 1, 2008
- Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. European Journal of Pharmacology June 6, 1995
and 3 more in the library